One third of U.S. men older than 65 yr have type 2. Low Testosterone in Men with Type 2 Diabetes: Significance and Treatment.

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1 SPECIAL Clinical FEATURE Review Low Testosterone in Men with Type 2 Diabetes: Significance and Treatment Mathis Grossmann Department of Medicine, Austin Health/Northern Health, University of Melbourne, Heidelberg, VIC 3084, Australia Context: The relationship between testosterone and diabetes in men is an important issue, given that one third of U.S. men aged 65 yr or older have diabetes, with a similar percentage having low testosterone levels. Evidence Acquisition: The medical literature from 1970 to March 2011 was reviewed for key articles. Evidence Synthesis: In population-based studies, low testosterone is commonly associated with type 2 diabetes and the metabolic syndrome, and it identifies men with an adverse metabolic profile. The difference in testosterone levels between men with diabetes compared to men without diabetes is moderate and comparable in magnitude to the effects of other chronic diseases, suggesting that low testosterone may be a marker of poor health. Although the inverse association of testosterone with diabetes is partially mediated by SHBG, low testosterone is linked to diabetes via a bidirectional relationship with visceral fat, muscle, and possibly bone. There is consistent evidence from randomized trials that testosterone therapy alters body composition in a metabolically favorable manner, but changes are modest and have not consistently translated into reductions in insulin resistance or improvements in glucose metabolism. Conclusions: The key response to the aging, overweight man with type 2 diabetes and subnormal testosterone levels should be implementation of lifestyle measures such as weight loss and exercise, which, if successful, raise testosterone and provide multiple health benefits. Although approved therapy for diabetes should be used, testosterone therapy should not be given to such men until benefits and risks are clarified by adequately powered clinical trials. (J Clin Endocrinol Metab 96: , 2011) One third of U.S. men older than 65 yr have type 2 diabetes (hereafter referred to as diabetes) (1), and a similar percentage have low or subnormal testosterone levels (2), compared with reference ranges based on healthy young men. Prevalence rates of diabetes in Europe and Oceania are similar to those in the United States; over the next 20 yr, the prevalence of diabetes is predicted to increase by 69% in developing countries and by 20% in developed countries (3). In addition, age-related decreases in testosterone are a global phenomenon in men, although there is evidence for geographical and racial variation (4). ISSN Print X ISSN Online Printed in U.S.A. Copyright 2011 by The Endocrine Society doi: /jc Received January 14, Accepted May 9, First Published Online June 6, 2011 Because diabetes and low testosterone commonly overlap in such men, the clinician is commonly faced with the question of whether testosterone therapy should be considered. There has been vigorous debate as to what extent low testosterone causally contributes to diabetes and its complications, or whether low testosterone is merely a biomarker, coexisting with diabetes because of in-common risk factors, or a consequence of the diabesity. Although the former may justify testosterone therapy, the risk-benefit ratio of such treatment can only be clarified by adequately designed randomized clinical trials. This re- Abbreviations: ADT, Androgen deprivation therapy; AR, androgen receptor; ARKO, AR knockout; BMI, body mass index; CI, confidence interval; DHT, dihydrotestosterone; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model of assessment for insulin resistance; MetS, metabolic syndrome; RCT, randomized, placebo-controlled trial. J Clin Endocrinol Metab, August 2011, 96(8): jcem.endojournals.org 2341

2 2342 Grossmann Testosterone in Diabetes J Clin Endocrinol Metab, August 2011, 96(8): view will discuss the evidence from observational studies associating low testosterone with diabetes, possible mechanisms underpinning this relationship, and results from intervention trials, and conclude with recommendations for clinical practice and further research. The material presented in this review is based on peerreviewed journals indexed on the PubMed database from 1970 to March Multiple searches were performed using the terms diabetes, testosterone, androgen, insulin resistance, and males. In addition, references listed in meta-analyses and systematic reviews of androgen deficiency and treatment in men were reviewed. Low Testosterone and Diabetes: Population-Based Studies Cross-sectional studies A meta-analysis by Ding et al. (5) analyzed 20 crosssectional studies with a total of 850 men with diabetes and 2000 nondiabetic controls. Individual studies included in this meta-analysis were small, with a mean of 39 diabetic patients per study (range, 8 155), and consisted of highly selected populations and convenience samples. Nevertheless, total testosterone levels were consistently lower in diabetic men compared with nondiabetic controls in all individual studies, with a mean pooled difference of 2.66 nmol/liter [95% confidence interval (CI), 3.45 to 1.86]. The difference in total testosterone was less, 1.61 nmol/liter (95% CI, 2.56 to 0.65), but was still significant after adjustment for age and crude measures of body fat, such as body mass index (BMI) and waist circumference. These findings were confirmed by a more recent meta-analysis of 28 cross-sectional studies including 1,822 men with diabetes and 10,009 nondiabetic controls by Corona et al. (6); total testosterone was lower in men with diabetes compared with controls [mean difference, 2.99 nmol/liter (95% CI, 3.59 to 2.40)], and diabetes remained associated with lower total testosterone levels independent of age and BMI (adjusted r 0.568; P ) (6). Neither Ding et al. (5) nor Corona et al. (6) analyzed the association of free testosterone levels with diabetes, due to the lack of reliable data. However, a crosssectional study from the Third National Health and Nutrition Examination Survey (NHANES) cohort including 1413 adult men, 101 of which had diabetes, showed that men in the lowest tertile of calculated free testosterone, adjusted for age, ethnicity, and adiposity, were more likely to have prevalent diabetes (odds ratio, 4.12; 95% CI, ; P 0.04) (7). In addition, a recent crosssectional analysis of 1292 men from the Norfolk population found that the 156 men with a hemoglobin A1c (HbA1c) of at least 6.5% or self-reported diabetes had, compared with men with an HbA1c no greater than 5%, a 2.4 nmol/liter lower circulating total and a 30 pmol/liter lower free testosterone level, respectively (P 0.001) (8). Other recent cross-sectional studies included larger numbers of men with diabetes, between 100 and 580, but were limited by the absence of a nondiabetic control group. These studies from Australia (9), the United Kingdom (10), and the United States (11) consistently showed that 30 50% of aging, obese men with diabetes, in the absence of known testicular or pituitary pathology, have low total or free testosterone, at least relative to reference ranges based on healthy young men. The degree of hypotestosteronemia, however, was moderate, with mean total testosterone levels ranging from nmol/liter (9 11). In these men, similar to what is found for men without diabetes, the prevalence of low testosterone increases with age and adiposity, so that in one study, two thirds of men who were older than 65 yr or obese had low testosterone (9). Observational studies consistently show that obesity is a major determinant of low testosterone, even overriding the effects of age, noting the opposite effects on SHBG, which is arguably the strongest determinant of circulating testosterone (12 14). The association of obesity itself with TABLE 1. Prospective studies assessing the relationship of testosterone levels with future risk of diabetes First author (Ref.) Diabetes present No. of patients Age (yr) BMI (kg/m 2 ) Total T (nmol/liter) Yes No Yes No Yes No Yes No Haffner (16) a a 19.4 Stellato (17) a a 18.3 Oh (18) N.R. N.R. Laaksonen (19) a a 20.4 Vikan (20) a a 13.6 Lakshman (21) N.R. N.R. N.R. N.R a 18.3 Follow-up ranged from 5 to 17 yr. Level of adjustment varied between studies and included age, BMI, waist circumference, and comorbid conditions. T, Testosterone; N.R., not reported. a P 0.05.

3 J Clin Endocrinol Metab, August 2011, 96(8): jcem.endojournals.org 2343 low testosterone was highlighted by the largest case-control study to date, including 400 diabetic men and 1400 nondiabetic controls (15). Although 51% of diabetic men (mean BMI, 32 kg/m 2 ) had low free testosterone, it was also low in 30% of the nondiabetic controls (BMI, 29 kg/m 2 ). Nevertheless, diabetic men still had significantly lower total and free testosterone than controls, even after adjusting for BMI, although the difference for total testosterone was 0.8 nmol/liter, half of that reported in the meta-analysis of Ding et al. (5). Prospective studies In Ding s meta-analysis of prospective studies, men with total testosterone levels above 15.5 nmol/liter had a 42% lower risk of incident diabetes (relative risk, 0.58; 95% CI, 0.39 to 0.87) compared with men with a total testosterone of no greater than 15.5 nmol/liter (5). In the meta-analysis Corona et al. (6), baseline total testosterone was 2.08 nmol/liter (95% CI, 3.57 to 0.59) lower in men who developed diabetes compared with those who did not. Although these meta-analyses did not address the association of free testosterone levels with future diabetes, this has been reported by six prospective studies (Table 1) (16 21). After adjusting for confounders, the inverse relationship of free testosterone with future diabetes diminished, and low free testosterone independently predicted diabetes in only one study (17). A major reason for this diminished relationship was adjustment for central fat by waist circumference. In addition, individual studies lacked power because only a few men developed diabetes during the studies. Low Testosterone and the Metabolic Syndrome (MetS): Population-Based Studies The MetS is closely associated with and often precedes diabetes, and therefore, studies assessing testosterone levels had larger numbers of affected men compared with studies in diabetic men. In a recent cross-sectional study of 1226 men from the NHANES cohort, both total and free testosterone levels were inversely correlated with the presence of the MetS. However, after adjustment for possible confounders including waist circumference and insulin resistance [by homeostasis model of assessment for insulin resistance (HOMA-IR)], only total (but not free) testosterone remained inversely associated with the MetS (22). In a recent meta-analysis of 52 observational studies comprising 22,043 men, both total testosterone levels (mean difference, 2.64 nmol/liter; 95% CI, 2.95 to 2.32) and free testosterone levels (mean standardized difference, 0.26 pmol/liter; 95% CI, 0.39 to 0.13) were lower in men with compared with men without the MetS (23), but adjustment for confounders was less comprehensive than for the NHANES cohort. Moreover, a metaanalysis of longitudinal studies showed that baseline total testosterone was 2.17 nmol/liter lower in men with incident MetS compared with controls (P ) (24). In two prospective studies, low baseline free testosterone levels independently predicted the MetS in one study (19) but not in the other (25). Conclusion from Population-Based Studies First, there is consistent observational evidence that low testosterone is associated with and predicts diabetes and the MetS. However, the strength of the associations is moderate, corresponding to a decrease of 2 3 nmol/liter in total testosterone. This is similar to the decrease found in other chronic diseases such as chronic obstructive pulmonary disease, HIV/AIDS, and renal failure, conditions in which the prevalence of low testosterone levels ranges from 20 70% (26). This suggests that, at least in part, this moderate hypotestosteronemia is a nonspecific effect of chronic illness. TABLE 1. Continued Free T (pmol/liter) SHBG (nmol/liter) Adjusted odds ratio (95% CI) Yes No Yes No Total T Free T SHBG 660 a a ( ) 1.28 ( ) 1.64 ( ) a 305 a a 32.2 N.S ( ) a 1.89 ( ) N.R. N.R. N.R. N.R. 2.7 ( ) a 0.80 ( ) N.R a ( ) a 1.42 ( ) 3.60 ( ) a a ( ) 0.87 ( ) 1.35 ( ) a ( ) a 1.03 ( ) 2.00 ( ) a

4 2344 Grossmann Testosterone in Diabetes J Clin Endocrinol Metab, August 2011, 96(8): Second, this inverse association between testosterone and diabetes/the MetS is stronger for total compared with free testosterone, which implies a role for SHBG given that total but not free testosterone changes in parallel with SHBG. Third, this association is weakened by adjustment for waist circumference, suggesting a role for abdominal fat. The effects of changes in abdominal fat and SHBG levels on testosterone are discussed below. Limitations of Population-Based Studies Observational studies, even if prospective, cannot inform about causality, let alone direction of causality, given the inability to exclude residual confounding by imperfect measurement of known or unknown pathogenic factors. Given that the disease process leading to diabetes starts years before diagnosis, prodromal metabolic changes not assessed in these studies may be a partial explanation for apparent causation. Thus, the evidence is consistent with the possibility that low testosterone may contribute to, or be a very early consequence of, pathogenic mechanisms that ultimately lead to diabetes. Other limitations, discussion of which is beyond the scope of this review, include analytical shortcomings in adjustment for confounders; choice and precision of testosterone assays (27), including free testosterone (28); reliance of single testosterone measurements; and diagnosis of diabetes by self-report. Low Testosterone and Diabetes: Potential Mechanisms Role of SHBG All prospective studies that analyzed both SHBG and testosterone consistently showed that low SHBG predicted diabetes (Table 1) (16 21) and the MetS (19, 25) more strongly than low testosterone. Evidence for a potential causal role for low SHBG in the development of diabetes comes from the identification of genetic SHBG variants that are concordantly predictive of both SHBG levels and diabetes risk (29, 30). Furthermore, in a prospective study, the association of low SHBG with diabetes risk persisted after adjustment for both free [hazard ratio, 2.04 (95% CI, )] and total [hazard ratio, 1.95 (95% CI, )] testosterone levels, whereas testosterone was not associated with diabetes independently of SHBG (21). Consistent with a pathogenic role of low SHBG in diabetes, in a cross-sectional study of diabetic men, low SHBG (but not low testosterone) was independently associated with worse glycemic control (9). However, given the strong inverse association of SHBG with insulin resistance and visceral adiposity, reverse causation or an in-common third factor cannot be excluded. Further study is required to assess whether SHBG levels add additional information to conventional risk factors for diabetes and related complications and whether SHBG mediates risk via androgenic or testosterone-independent mechanisms. It is also clear that the low testosterone-diabetes relationship is not solely due to SHBG; studies have shown that the inverse association of testosterone with insulin resistance and with the MetS is independent of SHBG (9, 31, 32). Role of visceral fat In observational studies, adjustment for waist circumference, a proxy of visceral abdominal fat, reduced but did not eliminate low testosterone-diabetes associations (Table 1). However, four cross-sectional studies in men with (33) or without (34, 35) diabetes or with Klinefelter s syndrome (36) that rigorously controlled for fat mass and distribution using computed tomography (34, 35), magnetic resonance imaging (33), or dual-energy x-ray absorptiometry (36) all showed that after adjustment for visceral adipose tissue, the inverse association of testosterone with insulin resistance was no longer significant, suggesting that this relationship is mediated through visceral fat. This pivotal inverse association of abdominal fat with low testosterone is supported by large cross-sectional surveys showing that the inverse association of testosterone with individual components of the MetS was the strongest for central adiposity (22, 37, 38) and that among multiple health variables, increased waist circumference was the most closely associated with low testosterone (39). Indeed, after computed tomography adjustment for visceral adiposity, the relationship of testosterone with age was eliminated (40). However, as discussed below, if central fat is a major mediator of this low testosterone- diabetes relationship, adjustment for fat could be considered an overadjustment because adjustment for variables within the causal pathway can obscure pathogenesis. Moreover, low testosterone was more strongly predictive of the MetS in lean, compared with overweight, men in one study, suggesting that this inverse association may not be solely dependent on regional fat distribution (25). Low Testosterone May Increase Insulin Resistance Elegant rodent work by Bhasin s group (41) has shown that, in vitro, testosterone promotes commitment of plu-

5 J Clin Endocrinol Metab, August 2011, 96(8): jcem.endojournals.org 2345 ripotent stem cells to the myogenic lineage but inhibits their differentiation into adipocytes via an androgen receptor (AR)-mediated pathway. These findings provide mechanistic insights into the well-documented effects of testosterone therapy on body composition in men, namely a reduction in fat mass and an increase in muscle mass, changes expected to decrease insulin resistance. In randomized, placebo-controlled trials (RCT) of testosterone therapy, however, these testosterone-mediated changes in body composition are modest, with a mean 1.6 ( 6.2%) to 2.0 kg decrease in total fat mass and a 1.6 kg ( 2.7%) to 2.7 kg increase in lean body mass (42, 43), and without consistent associations with decreased insulin resistance (see below). Strong evidence that very low (castrate) testosterone levels lead to increased insulin resistance comes from men with prostate cancer receiving androgen deprivation therapy (ADT). In prospective observational studies, 12 months of ADT increased fat mass by 9 14%, and decreased lean mass by %, with associated increases in insulin resistance (44, 45). Moreover, ADT has been associated with an increased risk of diabetes in several large cohort studies (46, 47). Similarly, male AR knockout (ARKO) mice had decreased muscle and increased fat mass, although whether these mice are insulin-resistant remains controversial (48 50). In addition to stem cell effects (41), testosterone decreases insulin resistance by regulating mature adipocytes and myocytes; testosterone enhances catecholamine-induced lipolysis in vitro (51) and reduces lipoprotein lipase activity and triglyceride uptake in human abdominal adipose tissue in vivo (52). Moreover, testosterone levels correlate positively with genetic and functional mitochondrial indices of increased insulin sensitivity in human skeletal muscle (32), and in male rats, castration increases insulin resistance by decreasing muscular glucose uptake (53). Recent microarray studies in mice have shown that testosterone regulates skeletal muscle genes involved in glucose metabolism in ways that would be expected to decrease systemic insulin resistance (54). Interestingly, transgenic male rats selectively overexpressing the AR in skeletal muscle have reduced amounts of body fat, suggesting that AR signaling in muscle cells is sufficient to decrease fat mass (55). This is consistent with the observation that male mice with a targeted deletion of the AR in adipose tissue have no measurable changes in body fat (56). There is also evidence that hepatic AR signaling may inhibit the development of insulin resistance (57), consistent with an inverse association of testosterone with hepatic steatosis in a cross-sectional study (58). Because body composition changes in global ARKO mice may be consequent in part with decreased physical activity (49), testosterone may also have central motivational effects. Recent work by Karsenty s group (59) has implicated the skeleton as a regulator of glucose metabolism as well as of testosterone, at least in male mice. An osteoblastsecreted molecule, osteocalcin, not only decreased insulin resistance but also stimulated testicular testosterone secretion by binding to a G protein-coupled receptor expressed on Leydig cells (60). Consistent with these rodent studies, observational studies in men have associated lower levels of osteocalcin with increased insulin resistance and fasting glucose and with the MetS (61, 62). However, whether low osteocalcin levels contribute to the inverse association of testosterone with insulin resistance in men is currently unknown. In summary, the bulk of the evidence suggests that testosterone decreases insulin resistance indirectly, via promotion of metabolically favorable changes in body composition, although other mechanisms may play a role. The extent to which models with extreme manipulations of testosterone levels such as ARKO mice and men with prostate cancer receiving ADT apply to most men with diabetes who have only mildly reduced testosterone levels is uncertain. The more consistent changes in insulin resistance during ADT compared with testosterone therapy may relate to the more significant changes in body composition in the former, due to the more dramatic changes in testosterone. Changes in Fat and Insulin Resistance: Effects on Testosterone Although the above studies show that changes in testosterone lead to changes in body composition and insulin resistance, there is also evidence for the reverse. Prospective, observational studies show that adiposity and the MetS predict the development of low testosterone levels (63, 64). Moreover, large prospective cohort studies in U.S. (65) and German (66) men showed that weight gain and development of diabetes or the MetS accelerated the age-related decline in testosterone, suggesting that this decline may be at least partially prevented through management of lifestyle factors. Similarly, in diabetic men followed longitudinally, changes in testosterone levels over time correlated inversely with changes in insulin resistance, suggesting that improved lifestyle factors or altered pharmacological management that improved insulin sensitivity also contributed to increased testosterone levels (9). Consistent with these observational studies are findings (discussed below) that both weight loss and exercise increase testosterone levels.

6 2346 Grossmann Testosterone in Diabetes J Clin Endocrinol Metab, August 2011, 96(8): Bidirectional Relationship of Testosterone and Adipose Tissue The current evidence is therefore consistent with a bidirectional relationship between visceral fat and testosterone, which sets up a self-perpetuating cycle promoting insulin resistance. Thus, increased visceral fat leads to increased secretion of proinflammatory cytokines, estradiol, insulin, and leptin, all of which may inhibit the activity of the hypothalamopituitary gonadal axis at multiple levels (67 70). Low testosterone promotes further accumulation of visceral fat, which, via increased inflammatory cytokines, increases insulin resistance and diabetes. Low testosterone may also increase insulin resistance via mechanisms involving muscle (32, 53), liver (57, 58), and bone (59, 60). Finally, low SHBG may lead to insulin resistance and to lower total testosterone (29). The fact that diabetic men usually have low LH levels (11) suggests that the predominant inhibition is central and is supported by the demonstration of reduced LH pulse amplitudes in morbidly obese men (71). In the very obese, increased estradiol, because of increased fat-expressed aromatase, decreases gonadotropin levels and thus testosterone, evidenced by the fact that treatment with aromatase inhibitors can normalize testosterone levels and restore spermatogenesis (72). However, insulin resistance also directly inhibits Leydig cell testosterone secretion, at least in nonobese men (73). Sex Steroid Actions beyond Circulating Testosterone It is well recognized that relating a serum testosterone level to a clinical phenotype is an oversimplification, given that circulating testosterone levels, whether free or total (28), are unlikely to accurately reflect androgen action at the tissue level. Indeed, testosterone not only directly transactivates the AR but also acts via dihydrotestosterone (DHT) and estradiol (74). DHT may mediate, at least in part, the metabolically favorable changes in body composition observed with testosterone therapy because, in a recent RCT of healthy men, DHT treatment significantly increased lean body mass and decreased fat mass, despite decreasing total testosterone to less than 5 nmol/liter (75). Furthermore, testosterone action is modulated by AR polymorphisms (76), as well as by transcriptional cofactors (74), likely in an age- and tissue-dependent fashion. Not surprisingly, therefore, circulating testosterone concentrations account for only 40 67% of the variance in fat-free mass and muscle size (77). In addition, local androgen synthesis and inactivation may not be reflected in circulating testosterone levels (78). The characterization of the role of estradiol in the regulation of glucose metabolism in males has been hampered both by its close association with adiposity and by difficulties in accurately measuring the very low levels circulating in men. In the meta-analysis of Ding et al. (5), estradiol levels were significantly higher in men with diabetes compared with nondiabetic controls, even after adjustment for BMI. This positive association of estradiol with diabetes has been confirmed in more recent crosssectional (79) and prospective (20) studies and remained significant after multivariate adjustment including waist circumference (20, 79). Thus, opposite associations of estradiol and testosterone with body fat and diabetes appear to be present in men. Lifestyle Measures: Effects on Testosterone Levels Given increasing evidence that obesity and disease are major determinants of the age-related decline in testosterone, it is not surprising that this decline can be at least partially prevented, or even reversed, by successful lifestyle measures. Indeed, weight loss, whether by diet or surgery, leads to substantial increases in total testosterone, especially in morbidly obese men, proportional to the amount of weight lost (Fig. 1) (80 87). Free testosterone rises less consistently, due to the concomitant increase in SHBG (Supplemental Table 1, published on The Endocrine Society s Journals Online web site at org). One study suggests that even smaller degrees of weight loss in only mildly overweight men significantly Total Testosterone Increase (nmol/l) a 82 84b Body weight lost (% of total) FIG. 1. Effect of weight loss on testosterone levels. Each data point refers to an individual study, and the size of the data point is proportional to the size of the study, ranging from 10 (87) to 58 men (83); refer to Supplemental Table 1. Numbers correspond to reference numbers as cited in the manuscript. The study by Khoo et al. (84) included two distinct populations of men depicted separately, men with (84a) and men without (84b) diabetes

7 J Clin Endocrinol Metab, August 2011, 96(8): jcem.endojournals.org 2347 increase testosterone levels (81). This disproportionate increase in testosterone relative to weight loss may have occurred because weight loss was achieved by exercise. Indeed, several uncontrolled studies have shown that exercise itself can increase testosterone by up to 30%, especially acutely (88). Moreover, the weight loss-induced increase in testosterone is associated not only with decreased insulin resistance but also with improved sexual function and lower urinary tract symptoms (84, 86). However, the effect of lifestyle measures on testosterone in men with only mild obesity requires further study. Effects of Testosterone Therapy on Glucose Metabolism: Intervention Trials Nonrandomized trials assessing the effects of testosterone therapy on insulin resistance, reviewed elsewhere (67, 69, 70, 89), yielded mixed findings. There have been eight larger RCT that have assessed effects of testosterone therapy on insulin resistance in men without diabetes (for review, see Ref. 67). Despite consistent metabolically favorable changes in body composition, decreases in measures of insulin resistance were found in only two of the eight trials, whereas the other six trials found no effect. Similarly, in a more recent, yet to be published 12-month RCT of 40 middle-aged obese men (mean BMI, 33.6 kg/m 2 ) with a mean baseline total testosterone level of 11.6 nmol/ liter, testosterone therapy, despite reducing total body fat by 10% and increasing muscle mass by 6%, had no effect on serum glucose or insulin levels (90). These trials suggest that testosterone therapy has limited effects on insulin resistance in men without diabetes. Furthermore, in a study of healthy young men with GnRH-induced androgen deficiency receiving testosterone add-back, insulin sensitivity did not change over a wide dose range of testosterone, despite an inverse correlation of testosterone levels with fat mass (91). The above trials recruited relatively healthy men with only mildly reduced testosterone levels, leaving the possibility that men with lower testosterone and more pronounced insulin resistance may derive a more significant benefit. Several recent RCT have assessed testosterone therapy specifically in men with diabetes or the MetS (Table 2) (92 97). A small pilot trial showed significant but small reductions in waist circumference, insulin resistance, and HbA1c (92), findings not confirmed by a similar trial in an Indian population (93). However, these men were unusually young and lean, and it is unclear whether therapeutic testosterone levels were achieved (93). Moreover, if testosterone reduces insulin resistance consequent to changes in body composition, 3 months of therapy may be too short to see the full effect, especially because fat mass continues to decrease beyond 6 months of testosterone therapy (98). Indeed, three recent larger RCT of longer duration consistently showed small, but significant decreases in insulin resistance (95 97) (Table 2). A significant decrease in HbA1c was seen in one trial (96), but not in a larger trial (97). In an unpublished, industry-sponsored RCT of 180 diabetic men, 26 wk of testosterone gel had no significant effect on HOMA-IR or HbA1c, despite a significant increase in lean body mass in testosterone-treated men ( pdf/1/3/4/4/2/s pdf) (Table 2). Overall, testosterone-induced changes in glucose metabolism appear inconsistent and less pronounced than would be expected from successful lifestyle programs (99 101), metformin (102), or glitazones (103), although trials that directly compare testosterone therapy to lifestyle intervention or insulin sensitizers are lacking. Whether the intensive lifestyle programs in such trials can be translated into clinical practice remains a major question. The important question of whether testosterone therapy enhances the effects of diet and exercise has been addressed in only one study of 32 men with newly diagnosed diabetes, but the control group did not receive placebo, and the trial was not double-blinded (94). The finding that waist circumference, HbA1c, and insulin resistance decreased significantly more in the combined lifestyle-testosterone group compared with lifestyle advice-only group suggests that testosterone therapy may have added benefits to diet and exercise alone, although this finding needs confirmation. Overall, the finding from RCT that testosterone therapy led to more consistent improvements in body composition than in parameters of glucose metabolism are in line with results of meta-analyses of testosterone therapy that showed, despite increases in the lean body mass to fat ratio, no differences in fasting glucose or incident diabetes ( ). Testosterone-induced reductions of insulin resistance are likely to be more pronounced in men with a higher baseline amount of fat and lower testosterone levels who achieve therapeutic testosterone levels over longer periods of time. Testosterone Therapy: Risk-Benefit Ratio Given the large number of men potentially eligible to receive testosterone therapy, assessment of the risk-benefit ratio of testosterone therapy with respect to clinically meaningful endpoints is crucial. This is especially important because most treated men would be expected to require long-term testosterone therapy; a recent study has

8 2348 Grossmann Testosterone in Diabetes J Clin Endocrinol Metab, August 2011, 96(8): TABLE 2. the MetS RCT assessing the effect of testosterone therapy on glucose metabolism in men with type 2 diabetes or First author (Ref.) n Diagnosis Age (yr) BMI (kg/m 2 ) T-Rx type T-Rx duration (wk) Dropout % Kapoor (92) 24 T2D TE 200 mg im 2- weekly 12 0 Gopal (93) 22 T2D TE 200 mg im 2- weekly 12 0 Heufelder (94) 32 MetS and newly diagnosed Transdermal T 50 mg/d with 52 0 T2D DE compared to DE alone Kalinchenko (95) 184 MetS and T2D (28%) TU 1000 mg im 12-weekly 30 7 Aversa (96) 50 MetS and T2D (30%) TU 1000 mg im 12-weekly 52 8 Jones (97) c 220 T2D (62%) and/or MetS (80%) Transdermal T 60 mg/d Solvay RCT d 180 T2D N.R. N.R. Transdermal T 1% Effect is relative to control. Patients were included on the basis of subnormal testosterone levels and symptoms compatible with androgen deficiency. n, Number of patients; Rx, therapy; WC, waist circumference; T, testosterone; TE, T esters; DE, diet and exercise; TU, T undecanoate; N.R., not reported; N.S., not significant; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HCT, hematocrit; PSA, prostate-specific antigen; CRP, C-reactive protein; Tg, triglyceride; T2D, type 2 diabetes; IPSS, International Prostate Symptom Score. a P b P c No changes in concomitant medications were allowed in the first 6 months. The trial (97) was continued for an additional 26 wk, during which medication changes were allowed. At 12 months, HOMA-IR remained significantly improved ( 16.4%; P 0.006). HbA1c was reduced at 9 months with testosterone therapy ( 0.58%; P 0.005), but not at 12 months. At 12 months, total testosterone had increased to 19.5 nmol/liter in the testosterone-treated group, but there was no significant change is PSA. d Unpublished; accessed at confirmed that the effects of testosterone therapy in older men do not persist after cessation of treatment (107). No trial information is available that assesses the effects of testosterone therapy on diabetes-related complications, and such a trial would be a formidable undertaking. Effects of testosterone on lipid levels and blood pressure, arguably more important cardiovascular risk factors than glycemia (108), are minor and inconsistent ( ). Although low testosterone has been associated with increased mortality and increased cardiovascular disease in some observational studies, the absence of such a relationship in healthier men suggests that low testosterone is a marker of unmeasured confounders (74, 109). The Women s Health Initiative trials were a salient reminder of the pitfalls of predicting the effects of sex steroid therapy from observational studies. Indeed, a recent study in a select group of men found that testosterone therapy increased cardiovascular events (110); however, numbers were small, and the result may have been due to chance alone, given that a similarly designed study (111) and meta-analyses ( ) have not confirmed this. Although there is no clear evidence that testosterone causes harm, there is an equal lack of evidence that it provides important health benefits. Given the high prevalence of cardiovascular and prostate disease in aging men, even small increases in adverse events may outweigh benefits. For example, obligate monitoring of prostate health during testosterone therapy may detect incidental prostate cancer of unclear significance, creating anxiety and therapeutic dilemmas in older men. On the other hand, leaving diabetic men with subnormal testosterone levels untreated may cause equal harm because low testosterone has been associated with symptoms of androgen

9 J Clin Endocrinol Metab, August 2011, 96(8): jcem.endojournals.org 2349 TABLE 2. Continued Total T baseline (nmol/liter) Total T achieved (nmol/liter) HbA1c baseline (%) Effect on WC (cm) Effect on HOMA-IR Effect on HbA1c (%) Other reported effects a 1.7 a ( 39%) 0.37% a Decrease in total cholesterol ( 0.4 mmol/liter a ). No effect on LDL, HDL, Tg or blood pressure N.R. 7.0 N.S. N.S. N.S. No effects on lipids, blood pressure b (11.2 a DE) b ( 59%) 0.8% a Decrease in CRP b, increase in adiponectin a N.R. 4.6 b 1.7 a ( 31%) N.R. Decrease in body weight ( 3.9 kg b ). Decrease in IL-1 a, TNF- a, CRP b, but not in IL-6, IL-10. No effect on fasting glucose, lipids. Increase in HCT ( 2.0% b ). No change in IPSS, PSA b b 2.6 b (60%) 1.1% a Decrease in CRP b.no change in PSA, prostate volume. Increase in HCT ( 3.8%) a. No change in lipids, blood pressure b 6.7 N.S. 0.8 a (15%) N.S. Decrease in lipoprotein a a and in HDL a. No change in % body fat N.R N.R. N.S. N.S. 2.0 kg increase in lean body mass b deficiency (10), anemia (112), and reduced muscle strength (113) in such men. Thus, the current evidence does not adequately inform about the risk-benefit ratio of testosterone therapy to guide clinical decision-making. This is because RCT have not been designed or powered for clinically meaningful endpoints, and conclusions from meta-analyses are limited, given the nature of the studies analyzed. Recommendations for Clinical Practice and for Further Research Current U.S. Endocrine Society guidelines state that information about the risks and benefits of testosterone therapy in men with diabetes is either limited or not available (114). Recommended testosterone treatment thresholds for older men without classical hypogonadism due to testicular or pituitary pathology, not specific to diabetic men, range from nmol/liter, with considerable disagreement among experts due to the lack of evidence (114, 115). The decision to treat will be guided by treatment goals, including other potential benefits of testosterone not specific to men with diabetes, such as improved sexual function, bone density, and muscle strength (114), and by whether the physician and the patient place higher value on unproven benefits of therapy or on equally unproven harm. Although testosterone treatment thresholds need to be individualized, I would not routinely recommend testosterone therapy for most older diabetic men with sustained total testosterone levels within the controversial range of nmol/liter (114), until further evidence is available. However, given the potential benefits of testosterone therapy, such men should be enrolled in clinical trials wherever possible. In the light of this unfortunate evidence gap, therefore, the key response to the aging, obese man with diabetes and low-normal testosterone should be implementation of lifestyle measures that, if successful, can safely increase testosterone levels and result in other health benefits. Indications for testosterone therapy should be no different to men without diabetes and be reserved for clinical andro-

10 2350 Grossmann Testosterone in Diabetes J Clin Endocrinol Metab, August 2011, 96(8): gen deficiency with sustained, unequivocally low testosterone after appropriate diagnostic workup. Testosterone therapy should not be routinely given to men with diabetes and low-normal testosterone until benefit is confirmed by well-conducted clinical trials. Future clinical trials should first compare or combine testosterone therapy with lifestyle measures and/or insulin-sensitizing agents; second, target men with lower testosterone, larger amounts of visceral fat, and more pronounced insulin resistance; and third, be powered to address clinically important endpoints and thus inform about the risk-benefit ratio of testosterone therapy. Unless and until a definitive RCT eventuates, information from future trials can be improved by standardized, prospective endpoints facilitating future meta-analyses. Acknowledgments I am most grateful to Drs. David Handelsman and Jeffrey Zajac for their helpful comments. Address all correspondence and requests for reprints to: Dr. Mathis Grossmann; Department of Medicine Austin Health/ Northern Health, University of Melbourne, Studley Road, Heidelberg, VIC 3084, Australia. mathisg@unimelb.edu.au. This work was supported by the National Health and Medical Research Council of Australia and by the Royal Australasian College of Physicians. Disclosure Summary: I am the principal investigator of an investigator-initiated trial assessing the effects of testosterone therapy in men with type 2 diabetes and low testosterone levels supported by Bayer Schering Pharma AG, Berlin, Germany. References 1. 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