Testosterone and Metabolic Syndrome: A Meta‐Analysis Study

272

ORIGINAL RESEARCH—ENDOCRINOLOGY Testosterone and Metabolic Syndrome: A Meta-Analysis Study

jsm_1991

272..283

Giovanni Corona, MD,*† Matteo Monami, MD,** Giulia Rastrelli, MD,* Antonio Aversa, MD,‡ Yuliya Tishova, MD,§ Farid Saad, MD,¶ Andrea Lenzi, MD,‡ Gianni Forti, MD,* Edoardo Mannucci, MD,** and Mario Maggi, MD* *Andrology and Sexual Medicine Unit, Department of Clinical Physiopathology, University of Florence, Florence Italy; † Endocrinology Unit, Medical Department, Azienda Usl, Maggiore-Bellaria Hospital, Bologna, Italy; ‡Department of Medical Pathophysiology (DFM-Fisiopatologia Medica), Sapienza University, Rome, Italy; §The Faculty of Medical Staff Refresher Training People’s Friendship University of Russia, Moscow, Russia; ¶Bayer Schering Pharma AG, Berlin, Germany; Gulf Medical University, Ajman, UAE; **Diabetes Section Geriatric Unit, Department of Critical Care, University of Florence, Florence, Italy DOI: 10.1111/j.1743-6109.2010.01991.x

ABSTRACT

Introduction. Metabolic syndrome (MetS) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in MetS has not been completely clarified. Aim. To systematically analyse the relationship between androgen levels and MetS we performed a review and meta-analyses of available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was also performed. Methods. An extensive Medline search was performed including the following words “testosterone,” “metabolic syndrome,” and “males”. Main Outcome Measures. Out of 323 retrieved articles, 302 articles were excluded for different reasons. Among the 20 published studies included, 13, 3, and 4 were cross-sectional, longitudinal, and RCTs, respectively. Another unpublished RCT was retrieved on www.clinicaltrials.gov. Results. MetS patients showed significantly lower T plasma levels, as compared with healthy individuals. Similar results were obtained when MetS subjects with and without erectile dysfunction were analyzed separately or when NCEP-ATPIII MetS criteria were compared with other definitions. Meta-regression analysis demonstrated that type 2 diabetes (T2DM) increased the MetS-associated T fall. In a multiple regression model, after adjusting for age and BMI, both T2DM and MetS independently predicted low testosterone (adj. r = -0.752; P < 0.001 and -0.271; P < 0.05, respectively). Analysis of longitudinal studies demonstrated that baseline testosterone was significantly lower among patients with incident MetS in comparison with controls (2.17 [-2.41;-1.94] nmol/L; P < 0.0001). Combining the results of RCTs, TRT was associated with a significant reduction of fasting plasma glucose, homeostatic model assessment index, triglycerides, and waist circumference. In addition, an increase of high-density lipoprotein cholesterol was also observed. Conclusions. The meta-analysis of the available cross-sectional data suggests that MetS can be considered an independent association of male hypogonadism. Although only few RCTs have been reported, TRT seems to improve metabolic control, as well as central obesity. Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, and Maggi M. Testosterone and metabolic syndrome: A meta-analysis study. J Sex Med 2011;8:272–283. Key Words. Testosterone; Metabolic Syndrome; Meta-analysis; Erectile Dysfunction

Corona and Monami equally contributed to the paper.

J Sex Med 2011;8:272–283

© 2010 International Society for Sexual Medicine

273

Testosterone and Metabolic Syndrome Introduction

M

etabolic syndrome (MetS) is a cluster of risk factors including abdominal obesity, decreased ability to process glucose (increased blood glucose and/or insulin resistance), dyslipidemia, and hypertension. MetS is associated with a twofold increase of 5- to 10-year risk of cardiovascular diseases (CVD) [1]. Furthermore, the syndrome confers a fivefold increse in risk for type 2 diabetes mellitus (T2DM) [1]. Despite this evidence, the clinical use of this category, and in particular its utility as a predictor of CVD, has been the subject of vigorous criticism [2–6]. Accordingly, recent data from the RIVANA study, a survey involving 880 community-dwelling men, supported the construct that MetS is not better than the sum of components in addressing cardiovascular risk [7]. A large body of evidence suggests that erectile dysfunction (ED) and male hypogonadism are frequently associated with MetS [6,8–11]. The prevalence of ED in subjects with MetS ranges from 27% [12] to 80% [13] and it is strictly associated with the number of MetS components and with the endothelial function impairment [6,8–11]. In addition, prospective data from the Massachusetts Male Aging Study (MMAS), in a population-based cohort, observed at three different time points over approximately 15 years, showed that ED could also be predictive of incident MetS [14]. An association between MetS and hypogonadism is also emerging [15–23] even in subjects with sexual dysfunction [6,8–11,24–27]. The presence of hypogonadism in men with MetS and ED is associated with a greater severity of symptoms of sexual dysfunctions, other than ED [9]. Interestingly, ED and male hypogonadism have been recently recognized as possible predictors of forthcoming metabolic diseases and cardiovascular events [28–32]. Accordingly, ED subjects have been considered paradoxically “lucky” because this symptom might offer them the opportunity to screen for the presence of ED-associated morbidities, including hypogonadism [33,34]. The specific mechanisms through which hypogonadism might affect CV health have not been completely clarified, but both clinical and animal evidence shows that testosterone (T) exerts a favorable effect upon vascular reactivity, inflammation, cytokine production, and adhesion molecule expressions, as well as on serum lipid concentration and haemostatic factors [6]. It can be speculated that the presence of hypogonadism and ED in subjects with MetS

should alert clinicians that such people deserve a more intensive lifestyle changes at an early stage to delay progression to a higher risk category. Unfortunately, no study has specifically evaluated this point in subjects with ED, whereas only few randomized controlled trials (RCTs) on the metabolic effect of T replacement therapy (TRT) in subjects with MetS have been published [35–39]. Aim

In order to comprehensively assess the relationship between androgen levels and MetS, we performed a systematic review and meta-analysis of available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of available randomized clinical trials on TRT was also performed. Methods

A meta-analysis was performed including all prospective and cross-sectional studies comparing T levels in subjects with or without MetS. In addition, randomized clinical trials, either with a crossover or a parallel series design, enrolling patients with MetS, comparing TRT with placebo or none were also included. An extensive Medline search was performed including the following words “testosterone”, “metabolic syndrome” and “males”. The search up to May 1, 2010 was restricted to English-language articles and studies of human participants. The identification of relevant abstracts, the selection of studies based on the criteria described above, and the subsequent data extraction were performed independently by two of the authors (G.C., G.R.), and conflicts resolved by the third investigator (M.M.). The quality of randomized clinical trials was assessed using some selected parameters among those proposed by Jadad et al. [40]. Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov website and the results, when not already published, were obtained through a formal request to the authors. Statistical Analysis

Heterogeneity for cross-sectional studies was assessed using the I2 test for total T (TT). Considering that heterogeneity could not be excluded (I2 = 73.8%), standardized mean differences in TT between subjects with or without MetS, were calJ Sex Med 2011;8:272–283

274

Corona et al. UNPUBLISHED Studies N=40

PUBLISHED studies Medline search N=283

Ongoing N=17 Reviews or editorials N=101 Specific sub-population N=42 No results stratified for MetS N=72 Specific Sub-population N=5 No human studies N=6 No serum T data N=15

Children N=1

No SD available for T N=2 Women N=9

Only T adjusted data available N=3 Children N=9

Result not available N=7

Case reports N=7 Women N=6

TOTAL N=21

Retrieved N=20

Cross-sectional studies N=13

Longitudinal studies N=3

RCTs N=4

Retrieved N=1

RCTs N=1

Figure 1 Trial flow diagram. MetS = metabolic syndrome; T = testosterone; SD = standard deviation; RCTs = randomized clinical trials.

culated using a random effect model. Furthermore, meta-regression analysis was performed to test the effect of T2DM on TT levels. In addition, linear regression analysis model, weighting each study for the number of subjects enrolled, was performed to verify the independent effect of age, body mass index (BMI) and T2DM and MetS on TT levels. In longitudinal studies, after verifying heterogeneity (I2 = 96.2%), standardized mean differences in TT between incident cases of MetS and non-MetS controls were calculated using a random effect model. In RCTs, the lack of homogeneity (I2 = 81.3%), suggested the use of a random effect model to calculate the standardized difference in mean values of waist circumference, and other metabolic parameters induced by TRT. All analyses were performed using Comprehensive Meta-analysis Version 2, Biostat (Englewood, NJ, USA) and SPSS 17.0 (SPSS Inc., Chicago, IL, USA). Results

Out of 323 retrieved articles, 302 articles were excluded for different reasons. The total flow is J Sex Med 2011;8:272–283

summarized in Figure 1. The characteristics of the trials included in the meta-analysis are summarized in Tables 1–3. Among the 20 published studies included, 13, 3, and 4 were cross-sectional, longitudinal, and interventional studies, respectively. Another unpublished RCTs was retrieved on www.clinicaltrials.gov (see also Figure 1, Tables 2 and 3). Cross-sectional studies included 2,254 and 6,407 patients, with and without MetS, respectively. The Begg adjusted rank correlation test (Kendall tau 0.02; P = 0.45), calculated on the basis of TT in cross-sectional studies, suggested no major publication bias. Patients with MetS showed significantly lower TT plasma levels in comparison with healthy individuals (Figure 2). Similar results were obtained when analyzing separately subjects with and without ED or when National Cholesterol Education Program Adult Treatment Panel III (NCEPATPIII) criteria were compared with other MetS classifications (Figure 2). Sex hormone binding globulin (SHBG) and calculated free-T were available for three studies, respectively. Meta-analysis showed that both SHBG and calculated free-T were significantly lower in subjects with MetS (9.74

Kuopio, Finland

Adelaide, Australia

Florence, Italy

Beirut, Lebanon

Chianti, Italy

Sofia, Bulgary

Cross-sectional studies Laaksonen et al.* [15]

Chen et al.* [16]

Corona et al.* [24]

Gennagè-Yared et al.* [17]

Maggio et al.* [18]

Robeva et al.‡ [19]

Perth, Australia

Kuwait

Kaohsiung, Taiwan

Kuopio, Finland

Chubb et al.* [22]

Qadan et al.* [23]

Yeh et al.* [27]

Longitudinal studies Laaksonen et al.* [30]

NA

NA

NA

Yes

No

No

No

Yes

No

Yes

No

No

No

Yes

No

No

ED

5.8

5.0

11.0

—

—

—

—

—

—

—

—

—

—

—

—

—

99/417

480/524

147/555

38/65

97/3

602/1900

101/280

348/738

265/597

25/108

10/10

73/389

94/59

236/567

20/140

345/1551

MetS Y/N

NA

NA

NA

34.0

95.0

0

9.6

30.9

NA

NA

16.5

NA

NA

32.0

NA

NA

T2DM %

63.3

48.7

51.3

57.5

60.2

76.4

78.8

51.9

52.0

56.9

30.4

74.5

59.3

53.6

NA

52.7

Age (years)

26.0

26.4

26.2

25.1

NA

26.2

23.8

26.5

27.4

25.1

30.6

28.0

27.3

26.5

26.1

26.8

BMI (kg/m2)

18.3 ⫾ 6.4/ 20.4 ⫾ 6.9 15.5 ⫾ 3.0/ 17.7 ⫾ 3.0 12.6 ⫾ 2.1/ 14.8 ⫾ 1.2

17.6 ⫾ 6.8/ 21.6 ⫾ 7.4 12.1 ⫾ 3.6/ 14.2 ⫾ 4.7 13.2 ⫾ 5.9/ 17.2 ⫾ 6.3 12.3 ⫾ 3.7/ 14.1 ⫾ 4.0 13.7 ⫾ 4.8/ 14.9 ⫾ 4.4 12.1 ⫾ 3.7/ 21.5 ⫾ 7.5 15.1 ⫾ 5.5/ 15.8 ⫾ 5.8 13.8 ⫾ 4.4/ 15.9 ⫾ 4.9 13.6 ⫾ 6.0/ 17.4 ⫾ 7.2 13.2 ⫾ 0.6/ 16.0 ⫾ 0.4 14.0 ⫾ 4.9/ 16.7 ⫾ 5.7 10.1 ⫾ 7.4/ 18.7 ⫾ 11.8 12.2 ⫾ 5.7/ 16.0 ⫾ 5.8

Total T MetS/noMetS (nmol/L)

NA

NA

NA

NA

NA

NA

NA

39.9 ⫾ 1.6/ 53.9 ⫾ 1.2 36.8 ⫾ 14.0/ 45.5 ⫾ 17.0 NA

194.5 ⫾ 76.9/ 205.4 ⫾ 74.7 274.6 ⫾ 88.2/ 291.2 ⫾ 90.8 NA NA

NA

NA

NA

NA

34.0 ⫾ 13.7/ 41.0 ⫾ 15.5 NA

NA

NA

NA

SHBG MetS/noMetS (nmol/L)

NA

NA

NA

NA

NA

NA

NA

273.0 ⫾ 79.0/ 307.0 ⫾ 75.0 NA

Free T MetS/noMetS (nmol/L)

All data are reported as mean ⫾ standard deviation. ED = erectile dysfunction; MetS = Metabolic Syndrome; Y/N = yes/no; T2DM = type 2 diabetes mellitus; NA = not available; BMI = body mass index; T = testosterone; SHBG = sex hormone binding globulin;. MetS was defined according to the following criteria: *NCEP-ATPIII = National Cholesterol Education Program-Adult Treatment Panel [53]; †IDF = International Diabetes Federation [56]; ‡WHO = World Health Organization [54] criteria for MetS definition.

Baltimora, Maryland, USA

Taipei, Taiwan

Tang et al.* [21]

Rodriguez et al.* [32]

Florence, Italy

Corona et al.* [26]

Greifswald, Germany

New York, USA

Kaplan et al.* [20]

Haring et al.* [31]

Tsukuba, Japan

Suetomi et al. [25]

†

Location

Follow up (years)

Moderators and outcome variables in individual cross-sectional and longitudinal studies included in the meta-analysis

Source

Table 1

Testosterone and Metabolic Syndrome 275

J Sex Med 2011;8:272–283

276 Table 2

Corona et al. Characteristics of the randomized clinical studies included in the meta-analysis

Study (Ref.)

La Vignera et al. [36]

Heufelder et al. [35]

Aversa et al. [37]

Aversa et al. [38]

Tishova et al. UP [39]

Hypogonadism cutoff Drugs Dose

8 nmol/L T-gel 1% 50 mg/daily

12 nmol/L T-gel 1% 50 mg/daily

Comparator Randomization Blinding Drop-out Intention-to-treat

No TRT group NA OL A Yes

No TRT group A OL A Yes

11 nmo/L TU 1,000 mg/ 12 weeks Placebo A A A Yes

11 nmol/L TU 1,000 mg/ 12 weeks Placebo A A A Yes

12 nmol/L TU 1,000 mg/ 12 weeks Placebo A A A Yes

T = testosterone; TU = testosterone undecanoate in castor oil; TRT = testosterone replacement therapy; NA = not adequate; A = adequate; OL = open label.

[-13.15;-5.58] nmol/L; P < 0.0001 and -21.47 [-35.38;-7.56] pmol/L; P < 0.005, respectively). Meta-regression analysis on cross-sectional studies showed that differences in total T between subjects with or without MetS were significantly higher in those studies reporting a higher prevalence of type 2 diabetes (Figure 3). Interestingly, in a multiple regression model, adjusting for age and BMI, both MetS and type 2 diabetes were independently associated with lower TT levels (adj. r = -0.752; P < 0.001 and -0.271; P < 0.05, respectively). In longitudinal studies (N = 3), enrolling 726 subjects with incident MetS, and a total

Table 3

observational time of 9.5 years, baseline TT was significantly lower among patients with incident MetS in comparison with controls (TT = -2.17 [-2.41;-1.94] nmol/L; P < 0.0001). The five RCTs available enrolled 306 patients with MetS, with a mean follow-up of 58 weeks. Of those trials, three were placebo-controlled, whereas two open-label trial compared TRT with no treatment. In these trials—enrolling only patients with MetS—hypogonadism was defined according to different criteria and TRT was administered in different formulations and doses (Tables 2–3). Combining the results of those trials, TRT was associated with a significant reduction of

Outcome variables in individual randomized controlled studies included in the meta-analysis

Study (Ref.) Location # patients (ID/C) Trial duration (weeks) MetS definition Age (years) BMI end point (Kg/m2 ID/C) Waist end point (cm) Glycemia end point (mmol/L ID/C) HOMA index end point Total cholesterol end point (mmol/L ID/C) HDL cholesterol end point (mmol/L ID/C) Triglycerides end point (mmol/L ID/C) Systolic blood pressure end point (mm Hg, ID/C) Diastolic blood pressure end point (mm Hg, ID/C)

La Vignera et al. [36] Catania, Italy 7/5 52 NCEP-ATPIII 58.0 27.8 ⫾ 1.3/ 28.4 ⫾ 1.7 100.7 ⫾ 1.8/ 100.7 ⫾ 2.9 NA/NA 4.0 ⫾ 1.1/ 6.2 ⫾ 1.4 NA/NA 0.9 ⫾ 0.1/ 0.8 ⫾ 0.1 2.2 ⫾ 0.2/ 2.7 ⫾ 0.4 NA/NA NA/NA

Heufelder et al. [35]

Aversa et al. [37]

Aversa et al. [38]

Munich, Germany 16/16 52 IDF 56.6 30.0 ⫾ 5.5/ 29.0 ⫾ 3.0 93.0 ⫾ 4.0/ 100.0 ⫾ 4.0 6.0 ⫾ 0.8/ 6.6 ⫾ 0.8 3.0 ⫾ 1.1/ 4.8 ⫾ 1.3 NA/NA

Rome, Italy 32/10 52 IDF 56.5 30.0 ⫾ 5.5/ 29.0 ⫾ 3.0 101.0 ⫾ 6.0/ 106.0 ⫾ 12.0 5.4 ⫾ 1.1/ 6.0 ⫾ 0.9 3.0 ⫾ 1.1/ 4.8 ⫾ 1.3 6.0 ⫾ 0.8/ 5.9 ⫾ 1.1 1.5 ⫾ 0.2/ 1.4 ⫾ 0.2 1.7 ⫾ 0.6/ 1.7 ⫾ 0.6 140.0 ⫾ 10.0/ 136 ⫾ 16.0 86.0 ⫾ 6.0/ 84.0 ⫾ 10.0

Rome, Italy 40/10 104 IDF 57.9 29.0 ⫾ 3.0/ 30.5 ⫾ 6.0 97.0 ⫾ 7.0/ 108.5 ⫾ 8.0 5.2 ⫾ 0.4/ 5.9 ⫾ 0.4 1.9 ⫾ 3.5/ 4.8 ⫾ 0.3 5.1 ⫾ 0.7/ 5.1 ⫾ 1.3 1.2 ⫾ 0.2/ 1.2 ⫾ 0.2 1.6 ⫾ 1.1/ 1.7 ⫾ 0.3 141.0 ⫾ 10.0/ 136.0 ⫾ 12.0 80.0 ⫾ 6.0/ 83.5 ⫾ 10.0

1.4 ⫾ 0.1/ 1.2 ⫾ 0.1 1.8 ⫾ 0.4/ 2.6 ⫾ 0.4 138.0 ⫾ 5.6/ 139 ⫾ 5.6 80.0 ⫾ 5.6/ 81.0 ⫾ 5.6

Tishova Y et al., UP [39] Moscow, Russia 105/65 30 IDF 51.6 34.7 ⫾ 6.5/ 35.0 ⫾ 6.3 113.2 ⫾ 13.9/ 116.3 ⫾ 14.5 6.1 ⫾ 1.7/ 6.2 ⫾ 1.1 5.8 ⫾ 6.4/ 6.13 ⫾ 5.7 5.3 ⫾ 1.0/ 5.5 ⫾ 1.1 1.2 ⫾ 0.4/ 1.1 ⫾ 0.5 1.9 ⫾ 1.1/ 2.4 ⫾ 1.9 NA NA

All data are reported as mean ⫾ standard deviation. ID/C = Investigational Drug/Comparator; HDL = high-density lipoprotein; UP = unpublished; NCEP-ATPIII = National Cholesterol Education Program-Adult Treatment Panel [53]; IDF = International Diabetes Federation [56]; MetS = Metabolic Syndrome; BMI = body mass index; HOMA = homeostatic model assessment; NA = not available.

J Sex Med 2011;8:272–283

277

Testosterone and Metabolic Syndrome

Source

TT mean differences (nmol/L) -15 -10 -5 0

-20

Diff. in means LL, 95% CI

5

UL, 95% CI

Laaksonen et al., 2003 (15)

-4,00

-4,85

-3,15

Chen et al., 2005 (16)

-2,10

-4,25

0,05

Gannagè-Yared et al., 2006 (17)

-1,80

-3,04

-0,56

Maggio et al., 2006 (18)

-1,20

-2,32

-0,08

Robeva et al., 2006 (19)

-9,43

-14,61

-4,25

Kaplan et al., 2006 (20)

-2,06

-2,75

-1,37

Tang et al., 2007 (21)

-2,80

-2,90

-2,70

Chubb et al., 2008 (22)

-2,70

-3,21

-2,19

Qadan et al., 2008 (23)

-8,60

-17,23

0,03

Corona et al., 2006 (24)

-4,00

-4,94

-3,06

Suetomi et al., 2006 (25)

-0,72

-3,22

1,78

Corona et al., 2007 (26)

-3,80

-4,67

-2,93

Yeh et al., 2008 (27)

-3,80

-6,11

-1,49

OVERALL NO ED

-2,60

-3,15

-2,06

OVERALL ED

-3,51

-4,48

-2,53

OVERALL NCEP-ATPIII

-2,72

-3,19

-2,26

OVERALL NO NCEP-ATPIII

-3,99

-7,28

-0,69

OVERALL

-2,85

-3,34

-2,36

TT lower in cases

TT higher in controls

Figure 2 Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between metabolic syndrome and controls from cross-sectional studies. Mean differences are expressed overall and as a function of absence/presence of erectile dysfunction (ED) or National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATPIII)/no NCEPATPIII criteria for the definition of metabolic syndrome. The size of the circles reflects the sample dimension.

0

S: -0.04[-0.02;-0.07], p<0.001 I: -6.75[-2.17;-2.68], p<0.00001

Difference in means

-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 0

1.9

13.3

24.7

36.1

47.5

58.9

70.3

81.7

93.1

100

PREVALENCE OF T2DM Figure 3 Influence of type 2 diabetes mellitus (T2DM) on total testosterone weighted mean differences between metabolic syndrome and controls. The size of the circles reflects the sample dimension.

J Sex Med 2011;8:272–283

278 fasting plasma glucose, homeostatic model assessment (HOMA) index, triglycerides and waist circumference (Figure 4). In addition, an increase of high-density lipoprotein (HDL) cholesterol was also observed (Figure 4), whereas no significant difference was observed for total cholesterol, blood pressure, and BMI (not shown). Discussion

This is the first study simultaneously evaluating—through a systematic review and meta-analysis of both cross-sectional and longitudinal studies available—total T, free-T, and SHBG level differences between male subjects with or without MetS. Effects of TRT in the available randomized clinical trials including MetS patients were also meta-analyzed. We demonstrated that MetS is significantly associated with an overall lower TT (about 3 nmol/L), this difference being more evident in studies conducted in subjects with ED than in those without. The association among MetS, hypogonadism and ED is well recognized, in fact the syndrome is highly prevalent in subjects with ED and low T [6,8,9,11]. Hypogonadism is often screened in patients with ED as a possible cause of sexual dysfunction and as a modulator of therapeutic response to PDE5 inhibitors [9,41]; the present results suggest that T level, in patients with ED, could also be useful as an indicator of metabolic status. The American College of Physician’s clinical practice guidelines on hormonal testing and pharmacological management of ED did not recommend for or against routine use of hormonal blood test [42]. Our study demonstrates that hypogonadism should be ruled out in ED patients with MetS. The specific mechanisms linking MetS and male hypogonadism have not been completely clarified [6,8,9,11]. Low T could be considered one of the many adverse consequences of overweight and obesity [43]. On the other hand, hypogonadism could contribute to the accumulation of excess fat and to the reduction of insulinsensitive muscular mass, thus establishing a vicious cycle. We recently demonstrated in a rabbit model that experimental MetS (high-fat diet) induced hypogonadotropic hypogonadism, and that experimental hypogonadotropic hypogonadism (GnRH analog) induced a dramatic increase in visceral adiposity [44]. The present meta-analysis supports this complex inter-relationship between the two conditions. Data derived from the MMAS J Sex Med 2011;8:272–283

Corona et al. demonstrated that men who were consistently obese during 8–9 years of follow-up had a greater decline of both total and free T levels [45]; the present analytical review demonstrates that lower baseline T levels predict the incidence of MetS. Insulin resistance has been recently considered the common pathogenetic link between ED, MetS and male hypogonadism [6]. Accordingly, in insulin-resistant individuals, such as those with MetS, insulin-induced production of nitric oxide is impaired, whereas that of endothelin-1 is preserved [46]. Furthermore, insulin resistant states are associated with atherosclerosis, which could produce lesions on penile arteries, therefore inducing a reduction of penile blood flow. T levels positively correlate with insulin sensitivity, as measured with a hyperinsulinemic-euglycemic clamp, independently from body composition [47], whereas T therapy withdrawal [48] or androgen deprivation therapy for prostate cancer [49] are associated with impaired insulin sensitivity. Finally, insulin itself is capable of stimulating T production and, simultaneously, of inhibiting SHBG concentration [50]. Hence, insulin resistance associated with obesity could contribute to the low T levels seen in obese men. Accordingly, we demonstrated that SHBG levels were significantly lower in subjects with MetS. However, the association between MetS and reduced SHBGunbound T (calculated free-T) supports the concept of a true MetS-induced hypogonadism, which goes beyond the effect of the decreased SHBG. Insulin resistance is also the “primum movens” of type 2 diabetes mellitus. In a previous metaanalysis, Ding et al. [51] demonstrated that lower T levels characterize the diabetic condition. Interestingly, the present meta-regression analysis shows that TT differences between subjects with or without MetS are greater in presence of T2DM. Accordingly, we previously reported similar data in a large series of subjects consulting for sexual dysfunction [52]. To test the specific contribution of MetS and T2DM to low T, we performed here a multivariate analysis, introducing MetS and T2DM as covariates, along with age and BMI. We demonstrated that both MetS and T2DM are independently associated with male hypogonadism. These results confirm what obtained in animal models of both type 1 diabetes [53] and MetS [44]. Any definition of MetS is, at present, largely arbitrary and under debate. Besides the widespread used NCEP-ATPIII [54] criteria, many other

-0,15

0,41

OVERALL

Tishova et al., UP (39)

Aversa et al., 2010b (38)

Aversa et al., 2010a (37)

Heufelder et al., 2009 (35)

-7,47

-9,07

-3,10

-5,13

Tishova et al., UP (39)

-4

-1,18

1,27

-6,51

0,51

-4,23

2,76

-3 -1

0

1

OVERALL

Tishova et al., UP (39)

Aversa et al., 2010b (38)

Aversa et al., 2010a (37)

Heufelder et al., 2009 (35)

La Vigneraet al., 2009 (36)

0,14

0,23

0,20

-0,14

-0,07

0,00

0,00

0,08

0,10

Aversa et al., 2010b (38)

Tishova et al., UP (39)

OVERALL

0,24

-0,04

0,10 Aversa et al., 2010a (37)

0,28

0,16

0,22

Heufelder et al., 2009 (35)

0,17

Diff. in meanLL, 95% CIUL, 95% CI

-0,07

FavorsTRT Favors Comparator

-0.2 -0.15 -0.10-0.05 0 0.050.100.150.2 0.25 0.3

-0,43

-0,52

-0,10

0,00

-0,80

-0,48

-0,73

-0,97

-0,79

-0,43

-1,08

-0,82

-0,12

-0,07

0,59

0,43

-0,52

-0,14

0.2 0.4 0.6 0.8 Diff. in meanLL, 95% CIUL, 95% CI

FavorsTRT Favors Comparator

HDL-Cholesterolmeandifferences (mmol/L)

-0,79

1,60

-0,66

-0,98

-0,72

-0,81

-1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0

Triglyceridesmeandifferences (mmol/L)

0,05

-2,16

-2,20

-5,04

-2,62

-1,28

-3,62

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La Vigneraet al., 2009 (36)

Source

-1,48

-0,30

-2,85

-1,80

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-2,22

2 Diff. in meanLL, 95% CIUL, 95% CI

FavorsTRT Favors Comparator

-2

Figure 4 Weighted differences (with 95% confidence interval [CI]) of mean fasting glycemia, homeostatic model assessment index, triglycerides, high-density lipoprotein cholesterol and waist circumference at end point across randomized controlled trials. The size of the circles reflects the sample dimension.

FavorsTRT Favors Comparator

-16,49

-10,51

-9,77

-2,76

-11,50

OVERALL

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HOMA index meandifferences

Diff. in meanLL, 95% CIUL, 95% CI

Aversa et al., 2010b (38)

5

-5,00

0

Aversa et al., 2010a (37)

-5

-7,00

-10

Heufelder et al., 2009 (35)

-15

0,00

-20

-6

La Vigneraet al., 2009 (36)

Waistcircumferencemeandifferences (cm)

-0,83

-0,49

-0,44

0,15

-0,05

Source

La Vigneraet al., 2009 (36)

Source

FavorsTRT Favors Comparator

-0,04

Tishova et al., UP (39)

-0,49

-0,70

Aversa et al., 2010b (38)

OVERALL

-1,35

-0,60

Aversa et al., 2010a (37)

-0,96

-1,15

-0,60

-16 -14 -12 -10 -0.8 -0.6-0.4-0.2 0 0.2 0.4 0.6 Diff. in meanLL, 95% CIUL, 95% CI

Fastingglycaemia meandifferences (mmol/L)

Heufelder et al., 2009 (35)

Source

Testosterone and Metabolic Syndrome 279

J Sex Med 2011;8:272–283

280 definitions have been proposed, including those by the World Health Organization in 1999 [55] and the American College of Endocrinology (ACE [55]), requiring the presence of insulin resistance or impaired glucose tolerance, and the most recent one from the International Diabetes Federation (IDF; [57]), which designates central obesity as an essential requirement. Our data showed that MetS is associated with low T levels independently from the criteria applied, supporting the concept that MetS can be considered as an independent risk factor for male hypogonadism, as also recently recognized by guidelines of the most important Andrological Societies [41,58]. The analysis of the available RCTs demonstrated, for the first time, that TRT in subjects with MetS is able to improve central obesity, as well as other parameters related to insulin resistance. In fact, present meta-analysis documented reduction of visceral adiposity and HOMA index, along with fasting glycemia and triglyceride levels. Although larger placebo-controlled studies are advisable, it can be speculated that TRT in MetS might improve the efficacy of traditional treatments, at least partially, through the reduction of visceral adiposity. Accordingly, we reported similar data in an animal model of MetS, showing that T supplementation ameliorates visceral adiposity and glucose tolerance [44]. Central obesity (high waist circumference) is a better predictor of an increased cardiovascular risk than obesity per se [59,60]. Although we cannot speculate on possible cardiovascular benefits of TRT in hypogonadal patients, a higher CV mortality has been observed in patients with low T, either with or without ED (see for review [6,61]). A previous systematic review of RCTs evaluating the effect of TRT on middle-aged and aging men did not report any modification of HDL cholesterol, but a possible improvement of total cholesterol. We here report that TRT in patients with MetS is able to improve HDL cholesterol without any effect on total cholesterol [62]. We recently demonstrated that the use of statins, which is a cornerstone of the treatment of dyslipidemia, might be considered a possible confounder in evaluation of T levels [63]. Unfortunately, we were not able to obtain information on this specific point in the RCTs evaluated. Hence, the lack of the effect of TRT on total cholesterol can be explained, at least partially, considering the statin interference. Alternatively, the short duration of the trials and the limited number of patients enrolled might represent another possible bias. J Sex Med 2011;8:272–283

Corona et al. Furthermore, low HDL, but not total cholesterol, being one of the features of MetS, studies on this condition select patients who have greater margins of improvement for HDL than for total cholesterol. Finally, TRT in MetS had no significant effect on blood pressure (BP). The relationship between T levels and hypertension has not been completely clarified [64]. Although androgens have proven to contribute to the development and severity of hypertension in some genetic and non-genetic rat models [65,66], in a rabbit model of MetS T supplementation only partially ameliorates hypertension [44]. In addition, contrasting findings have been reported in human epidemiological studies. In particular, although some studies have shown reduced androgen levels in subjects with essential hypertension, as compared with normotensive subjects [67,68], another did not confirm this result [69]. We previously demonstrated that only pulse pressure (i.e., the arithmetic difference between systolic and diastolic BP), but not systolic or diastolic BP, is androgen-dependent [70]. No information on pulse pressure was available in the RCTs evaluated. Some limitations should be recognized. Potential selection bias and confounding factors may exist. Finally, the number and the duration of RCTs as well as the number of the patients enrolled is limited. Conclusions

The MetS (visceral obesity, high triglycerides/low HDL cholesterol, hyperglycemia, and hypertension) has been proposed as a category for identifying individuals with increased risk of diabetes and cardiovascular diseases. We now further demonstrate its challenging association with male hypogonadism, in particular in subjects with ED. Recognizing the association between MetS and hypogonadism in ED subjects is important for both sexual and general health, alerting the patient and the physician on the potential cardiovascular and metabolic risks associated with low T. In fact, high-risk ED individuals could be candidates for specific lifestyle changes (such as weight loss and physical exercise) and pharmacological interventions, behind those specifically designed for sexual dysfunction. It could be speculated that in patients with MetS, correction of some metabolic parameters could lead to an improvement of sexual dysfunction and maybe of the hypogonadal condition. Alternatively, T replacement in hypogonadal sub-

281

Testosterone and Metabolic Syndrome jects with MetS and ED might have positive effects not only in sexual fitness but also on several components of the syndrome, as glucose tolerance and visceral fatness. To summarize our meta-analysis: T = more fitness, less fatness. Hence, more prospective investigations on TRT in MetS are needed.

2

Acknowledgments

We would like to thank Roberto Bruzziches and Davide Francomano, Department of Medical Pathophysiology (DFM-Fisiopatologia Medica), Sapienza University, Rome, Italy and Sandro La Vignera, Endocrinology Unit, University of Catania, Catania Italy. Corresponding Author: Mario Maggi, Prof., Clinical Physiopathology, Andrology Unit, University of Florence, Viale Pieraccini 6, Florence 50139, Italy. Tel: +39 0554271415; Fax: +39 0554271413; E-mail: m.maggi@ dfc.unifi.it

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7

Conflict of Interest: None. 8

Statement of Authorship

Category 1 (a) Conception and Design Giovanni Corona; Mario Maggi (b) Acquisition of Data Giovanni Corona; Giulia Rastrelli; Antonio Aversa; Yuliya Tishova (c) Analysis and Interpretation of Data Giovanni Corona; Matteo Monami; Antonio Aversa; Farid Saad; Andrea Lenzi; Gianni Forti; Edoardo Mannucci; Mario Maggi

Category 2 (a) Drafting the Article Giovanni Corona; Giulia Rastrelli; Matteo Monami; Mario Maggi (b) Revising It for Intellectual Content Giovanni Corona; Edoardo Mannucci; Mario Maggi

Category 3

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(a) Final Approval of the Completed Article Giovanni Corona; Mario Maggi 16 References 1 Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr, International Diabetes Federation Task Force on Epidemiology and Prevention, Hational Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation,

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