Abstract
Objective
The role of testosterone (T) in regulating body composition is conflicting. Thus, our goal is to meta-analyse the effects of T supplementation (TS) on body composition and metabolic outcomes.
Methods
All randomized controlled trials (RCTs) comparing the effect of TS on different endpoints were considered.
Results
Overall, 59 trials were included in the study enrolling 3029 and 2049 patients in TS and control groups respectively. TS was associated with any significant modification in body weight, waist circumference and BMI. Conversely, TS was associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction of fasting glycaemia and insulin resistance. The effect on fasting glycaemia was even higher in younger individuals and in those with metabolic diseases. When only RCTs enrolling hypogonadal (total T <12 mol/l) subjects were considered, a reduction of total cholesterol as well as triglyceride (TGs) levels were also detected. Conversely, an improvement in HDL cholesterol levels as well as in both systolic and diastolic blood pressure was not observed.
Conclusion
Our data suggest that TS is able to improve body composition and glycometabolic profile particularly in younger subjects and in those with metabolic disturbances. Specifically designed studies are urgently needed to confirm this point.
Introduction
Obesity constitutes a major health problem, and it is a risk factor for cardiovascular (CV) events, type 2 diabetes mellitus (T2DM), certain types of cancer, sleep apnoea, osteoarthritis, and most of all, excess mortality (1, 2, 3, 4, 5).
Considering that obesity is the result of a difference between energy intake and expenditure, lifestyle interventions, aimed at reducing food intake and increasing exercise, are the foundations of obesity care. One systematic review of controlled trials of lifestyle interventions indicates that psychological therapy was associated with a 2.5% weight loss after 1 year and that a combination of the former with diet and physical exercise almost doubled weight loss (6). However in real life, diet, physical activity, psychological therapies or the combination thereof, over the long term unfortunately, fail (7, 8). Even medical interventions, with the exception of bariatric surgery, have shown limited success, in particular as far as pharmacological treatments are concerned. Numerous anti-obesity drugs have been developed in the last 20 years, but they have often been suspended from the market because of poor efficacy and/or insufficient safety. The ideal pharmacological intervention should provide a prompt (during the 1st month) and sustained weight loss (i.e., >5% body weight loss after 3–6 months), without significant adverse effects. This is a difficult goal to achieve because energy balance regulation is redundant and overlaps with the regulation of other vital systems. Meta-analyses of pharmacological interventions demonstrate that available anti-obesity medications, such as orlistat, result in a modest, although clinically significant, weight loss (2.5–5 kg at 1 year) (9, 10). Glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, show an efficacy greater than of orlistat, but average weight loss does not exceed 5% of initial body weight (11). Other drugs, such as lorcaserin and combinations of bupropion–naltrexone or phentermine–topiramate, have not been approved in many countries because of safety concerns. A recent meta-analysis, considering the effects of any behavioural or medical interventions on waist circumference (WC), demonstrates an average reduction of 3 cm in the active arm over placebo (12).
In BMI-matched obese subjects, men have a greater amount of visceral fat than women (13, 14). In men, visceral obesity is the main cause of age-related late-onset hypogonadism (LOH) (3, 15, 16, 17) and weight loss is the first avenue of its treatment (18). The relative risk of being hypogonadal is increased by a factor of three in overweight individuals and by a factor of six in obese European adults (19). On the other hand, hypogonadism is associated with a substantial increase in fat accumulation, in particular in the visceral stores. Recently, some observational studies in men with LOH reported a substantial weight loss with testosterone supplementation (TS, 17). Hence, the concept of TS as a new anti-obesity medication in men with LOH is growing (17). The anti-obesity activity of TS in hypogonadal men may be effective because, on one hand, it reduces abdominal fat accumulation and, on the other, it improves muscle mass and strength, facilitating adherence to exercise regimens designed to combat obesity (17). In two independent cohorts of hypogonadal obese men observed for up to 6 years, WC decreased by 11.56 cm and weight declined by 17.49 kg (15.04%), after testosterone undecanoate (TU) injections (20). Based on this report, results with TU in LOH-associated obesity seem superior to other lifestyle or medical interventions (see before) and comparable to those obtained with the most invasive therapies, such as bariatric surgery (21). However, randomized controlled trials (RCTs) showing TS-induced weight loss as the primary endpoint are still lacking and those reporting it as a secondary outcome are often conflicting: some show weight loss (22, 23), others weight gain (24, 25) and the vast majority a non-significant effect (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52). Similar information can be obtained by scrutinizing observational and registry studies (53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72).
Meta-analyses are a mainstay of evidence-based medicine, able to overcome marked between-study heterogeneity, useful in addressing questions for which multiple data sources are conflicting or when a variety of reports with low statistical power is available. In fact, pooling data can improve power and provide a convincing result. Surprisingly, meta-analyses investigating TS-induced weight loss in LOH are lacking. In addition, results from previous meta-analyses on the effects of TS on body composition and other metabolic parameters in LOH are outdated, essentially conflicting ((73, 74, 75, 76, 77), see Table 1). In addition, retrieved and analysed outcomes of interest were different from one meta-analysis to another and the effect of TS on BMI and WC were never reported (see Table 1). Other meta-analyses on the effects of TS on body composition and metabolism were focused on specific LOH subpopulations, such as T2DM (15, 78, 79), metabolic syndrome (MetS) (15, 80), the combination of the two (81), human immunodeficiency virus (HIV) (15, 82, 83) or chronic obstructive pulmonary disease (COPD) (15, 84).
Comparisons on available meta-analyses evaluating the relationship between testosterone supplementation (TS), body composition and metabolic outcomes.
| Whitsel et al. (73) | Isidori et al. (74) | Haddad et al. (75) | Fernández-Balsells et al. (76) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Level of baseline TT | Level of baseline TT | ||||||||
| General | <10 nM | >10 nM | Mixed | General | <10 nM | Mixed | |||
| Number of trials included | 19 | 29 | 30 | 51 | |||||
| Number of patients analyzed | 272 | 1083 | 1642 | 2679 | |||||
| Inclusion criteria | |||||||||
| Only hypogonadal included | Yes | No | No | Yes | |||||
| Mixed population included | No | Yes | Yes | No | |||||
| Level of baseline TT | <12 nM | <10 nM | |||||||
| Outcome analyzed | |||||||||
| Weight | NR | NR | NR | ↔ | NR | NR | NR | ||
| Waist circumference | NR | NR | NR | NR | NR | NR | NR | ||
| BMI | NR | NR | NR | NR | NR | NR | NR | ||
| Fat mass | NR | ↓ | ↓ | ↓ | NR | NR | NR | ||
| Lean mas | NR | ↔ | ↑ | ↑ | NR | NR | NR | ||
| Total cholesterol | ↓ | ↓ | ↔ | ↔ | ↔ | ↓ | ↔ | ||
| HDL | ↓ | ↔ | ↓ | ↔ | ↔ | ↔ | ↓ | ||
| LDL | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | ||
| Triglycerides | ↔ | NR | NR | NR | ↔ | ↔ | ↔ | ||
| Diastolic blood pressure | NR | NR | NR | NR | NR | NR | ↔ | ||
| Systolic blood pressure | NR | NR | NR | NR | NR | NR | ↔ | ||
| Fasting glucose | NR | NR | NR | NR | NR | NR | ↔ | ||
| HOMA index | NR | NR | NR | NR | NR | NR | NR | ||
| Insulin | NR | NR | NR | NR | NR | NR | NR | ||
NR, not reported; TT, total testosterone.
The aim of the present study is to meta-analyse the available evidence on the effects of TS on body weight and WC, including other parameters concerning body composition and metabolic outcomes.
Methods
This meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline (http://prisma-statement.org/documents/PRISMA%202009%20checklist.pdf) (85).
An extensive Medline, Embase and Cochrane search was performed including the following words ('testosterone'(MeSH Terms) OR 'testosterone'(All Fields)) AND ('body composition'(MeSH Terms) OR ('body'(All Fields) AND 'composition'(All Fields)) OR 'body composition'(All Fields) AND English(lang) AND 'male'(MeSH Terms)). The search accrued data from January 1, 1969 up to August 31, 2014. In addition, completed but still unpublished RCTs evaluating the effects of TS on different outcomes were identified through a search on the www.clinicaltrials.gov website. The identification of relevant studies was performed independently by two of the authors (VG, GC), and conflicts resolved by the third investigator (AA). We did not employ search software. We hand-searched bibliographies of retrieved papers for additional references. The principal source of information was derived from published articles; if data were missing from the publication, an attempt at retrieval was made through the clinicaltrial.gov website.
Study selection
We included all RCTs both placebo and not placebo controlled, comparing the effect of TS on different endpoints (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 86, 87, 88, 89, 90, 91, 92, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113) (see also Fig. 1 and Tables 2, 3, 4). Observational studies (53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128) or studies not specifically evaluating body composition or glycometabolic outcomes were excluded from the analysis ((129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139); see also Fig. 1 and Table 5). Studies using androgens other than TS as well as studies with simultaneous treatment with other hormones and drugs were also excluded, unless there was a clearly defined treatment arm that received only T treatment. In addition, since phosphodiesterase type 5 inhibitors (PDE5is) have been reported to play a possible positive influence on metabolic outcome (140, 141), trials evaluating the effect of TS as an add-on to PDE5is were excluded from the analysis (see also Table 5).
Flow diagram of trial. Unpublished studies were identified through a search of www.clinicaltrials.gov website. N, number; GnRH, gonadotropin-releasing hormone; Gn, gonadotropins.
Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0262
Flow diagram of trial. Unpublished studies were identified through a search of www.clinicaltrials.gov website. N, number; GnRH, gonadotropin-releasing hormone; Gn, gonadotropins.
Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0262
Flow diagram of trial. Unpublished studies were identified through a search of www.clinicaltrials.gov website. N, number; GnRH, gonadotropin-releasing hormone; Gn, gonadotropins.
Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0262
Characteristics of the clinical studies included in the meta-analysis.
| Study (arm) (ref.) | Number patients (T/placebo or controls) | Trial duration (months) | Age (years) | Type of population | Baseline total T (nmol/l) | T levels | Dose | Placebo |
|---|---|---|---|---|---|---|---|---|
| (27) | 11/11 | 8 | 59.9 | Overweight/obesity | 15.8 | Mixed | TU oral 160 mg/day | Yes |
| (26) | 13/13 | 6 | 66.7 | Elderly men | 11.4 | Mixed | TE 100 mg/week | Yes |
| (28) | 9/9 | 9 | 57.2 | Obesity | 14.8 | Mixed | T gel 125 mg/day | Yes |
| (29) | 8/6 | 3 | 76.5 | Elderly men | 9.4 | <12 nM | TE 200 mg/2 weeks | No |
| (30) | 13/0 | 6 | 30.2 | Healthy | 20.7 | Eugonadism | TE 200 mg/week | No |
| (86) | 15/0 | 12 | 61 | Asthma+GC therapy | 12.3 | Mixed | Mixed ester 250 mg/month | No |
| (31) | 17/15 | 12 | 66.4 | Elderly men | 9.1 | <12 | TC 200 mg/2 weeks | Yes |
| (87) | 17/17 | 2 | 66.9 | Elderly men | 10.1 | Mixed | TU 120 mg/day | Yes |
| (24) | 7/7 | 3 | 66.7 | Elderly men | 11.2 | Mixed | TE 200 mg/2 weeks | Yes |
| (32) | 11/10 | 3 | 27 | Healthy | – | Eugonadism | TE 3.5 mg/kg per 2 weeks | Yes |
| (88) | 13/0 | 7 | 34.5 | LOH | 2.9 | <3.6 | TU 160 mg/day | No |
| (88) | 15/0 | 7 | 31.8 | LOH | 2.3 | <3.6 | TE im 250 mg/3 weeks | No |
| (88) | 15/0 | 7 | 35.8 | LOH | 2.7 | <3.6 | TPEL 1200 mg subcutaneous | No |
| (33) | 54/54 | 36 | 73.1 | Elderly men | 12.6 | Mixed | T patch 6 mg/day | Yes |
| (25) | 151/0 | 6 | – | LOH | 8.4 | <10.4 | T gel 50–100 mg/day | No |
| (25) | 76/0 | 6 | – | LOH | 8.2 | <10.4 | T patch 10 mg/day | No |
| (89) | 34/33 | 12 | 75.5 | Elderly men | 13.4 | Mixed | T patch 5 mg/day | Yes |
| (90) | 6/6 | 3 | 54.1 | LOH | 8.2 | <12 | T gel 125 mg/die | Yes |
| (91) | 21/17 | 6.5 | 70 | Elderly men | 14 | Mixed | TE 100 mg/2 weeks | Yes |
| (34) | 24/24 | 3 | 57.5 | T2DM, obesity | 9.45 | Mixed | TU oral 120 mg/day | No |
| (92) | 18/16 | 12 | 59.3 | Long-term GC therapy | 13.7 | Mixed | Mixed ester 200 mg/2 weeks | Yes |
| (35) | 7/5 | 6 | 67.6 | Elderly men | 12.3 | Mixed | TE 200 mg/2–3 weeks | Yes |
| (36) | 17/17 | 1 | 67 | Elderly men | 9.6 | Mixed | Mixed ester 250–500 mg/week | Yes |
| (93) | 140/0 | 3 | 57.8 | LOH | 7.9 | ≤10.4 | T gel 50–100 mg/day | No |
| (93) | 68/0 | 3 | 57.9 | LOH | 7.9 | ≤10.4 | T patch 5 mg/day | No |
| (94) | 33/6 | 3 | – | LOH | 8.9 | Mixed | TU oral 160 mg/day | Yes |
| (37) | 307/99 | 3 | 58 | LOH | 8.1 | <10.4 | T gel 50–100 mg/day or T patch 5 mg/day | Yes |
| (95) | 39/37 | 12 | 68.5 | Elderly men | 16.8 | Mixed | TU oral 160 mg/day | Yes |
| (38) | 12/12 | 2.5 | 67.1 | COPD | 10.4 | Mixed | TE 100 mg/week | Yes |
| (38) | 11/12 | 2.5 | 66.1 | COPD | 11.6 | Mixed | Training±TE 100 mg/week | Yes |
| (23) | 15/14 | 6.5 | 65.9 | COPD | 21.1 | Eugonadal | TE 250 mg/4 weeks | Yes |
| (96) | 123/0 | 42 | 51.5 | LOH | 9.2 | <10.4 | T gel 5, 7.5 or 10 g/day | No |
| (39) | 24/24 | 36 | 70.9 | Elderly men | 9.8 | <12 | TE 200 mg/2 weeks | Yes |
| (40) | 23/20 | 6 | 69.9 | Elderly men | 17.4 | Eugonadal | T patch 5 mg/day | Yes |
| (97) | 27/27 | 3 | 64 | T2DM | 8.7 | <12 | Mixed ester 200 mg/2 weeks | Yes |
| (98) | 17/19 | 3 | 72.5 | Elderly men | 14.4 | Mixed | Training±T patch 5 mg/day | Yes |
| (98) | 17/17 | 3 | 72 | Elderly men | 14.1 | Mixed | T patch 5 mg/day | Yes |
| (99) | 30/32 | 24 | 66.7 | Elderly men | 13.2 | Mixed | T patch 5 mg/day | Yes |
| (41) | 13/13 | 3 | 74.1 | Heart failure | 14.3 | Mixed | Mixed ester 250 mg/2 weeks | Yes |
| (100) | 13/13 | 13 | 68.9 | Elderly men | 8.5 | <11 | TU 1000 mg/12 weeks from week 6 | Yes |
| (42) | 31/31 | 12 | 63.3 | Elderly men | 13.5 | Mixed | T patch 5 mg/day | Yes |
| (101) | 120/117 | 6 | 67.3 | Elderly men | 10.8 | Mixed | TU oral 160 mg/day | Yes |
| (102) | 20/0 | 7.5 | – | LOH | – | <8 | TU 1000 mg/6–9 weeks | No |
| (102) | 20/0 | 7.5 | – | LOH | – | <8 | TE 250 mg/3 weeks | No |
| (43) | 17/18 | 13 | 69 | Elderly men | 8.4 | <11 | TU 1000 mg/12 weeks from week 6 | Yes |
| (44) | 35/35 | 3 | 71 | Heart failure | 7.9 | Mixed | TU 1000 mg/12 weeks from week 6 | Yes |
| (103) | 16/16 | 12 | 56.6 | T2DM | 10.4 | <12 | T gel 50 mg/day | No |
| (104) | 7/6 | 13 | 64.8 | Stable chronic angina | 9.8 | <12 | TU 1000 mg/12 weeks from week 6 | Yes |
| (105) | 32/10 | 6 | 57.8 | MetS and/or T2DM | 10.9 | <11 | TU 1000 mg/12 weeks from week 6 | Yes |
| (106) | 40/10 | 12 | 57.2 | MetS and/or T2DM | 10.1 | <11 | TU 1000 mg/12 weeks from week 6 | Yes |
| (107) | 22/22 | 3 | 44.2 | T2DM | 10.4 | Mixed | TC 200 mg/2 weeks | Yes |
| (45) | 113/71 | 7.5 | 52.1 | MetS | 6.7 | <12 | TU 1000 mg/12 weeks from week 6 | Yes |
| (108) | 69/62 | 12 | 77.9 | frailty, low BMD | 13.3 | Mixed | T gel 50 mg/day | Yes |
| (109) | 138/136 | 6 | 73.8 | Elderly frail men | 13.8 | Mixed | T gel 50 mg/day | Yes |
| (110) | 108/112 | 12 | 59.9 | MetS and/or T2DM | 9.4 | Mixed | T gel 60 mg/day | Yes |
| (111) | 130/132 | 6 | 73.9 | elderly frail men | 10.9 | Mixed | T gel 50 mg/day | Yes |
| (46) | 8/8 | 5 | 69 | Elderly men | 11.9 | Mixed | TE 100 mg/week | Yes |
| (47) | 23/23 | 6 | 67.5 | Elderly men | 12.1 | Mixed | T gel 50–100 mg/day | Yes |
| (48) | 33/34 | 4.5 | 48.5 | Obesity with OSAS | – | Mixed | TU 1000 mg/6 weeks | Yes |
| (49) | 237/79 | 12 | 58.7 | Elderly men | 12.8 | Mixed | TU 80–240 mg/day | Yes |
| (112) | 20/18 | 6 | 67 | Elderly men | – | Mixed | T gel 50–100 mg/day | Yes |
| (112) | 7/9 | 6 | 67 | Elderly men | – | Mixed | T gel 50–100 mg/day+training | Yes |
| (50) | 97/102 | 7.5 | 61.6 | T2DM | 9.2 | Mixed | TU 1000 mg/12 weeks from week 6 | Yes |
| (51) | 56/28 | 12 | 66 | Elderly men | 10.3 | <12 | Training en12 weeks from week | Yes |
| (51) | 55/28 | 48 | 66 | Elderly men | 10.3 | <12 | T gel 25–100 mg/day | Yes |
| (113) | 60/60 | 12 | – | Elderly men | – | <12 | TU 1000 mg/12 weeks from week 6 | Yes |
| (22) | 12/12 | 13.5 | 56.9 | LOH, obesity | 8.4 | <12 | TU 1000 mg/12 weeks from week 6 | No |
| (52) | 45/43 | 10 | 62 | T2DM | 8.6 | <12 | TU 1000 mg/12 weeks from week 6 | Yes |
TE, testosterone enanthate; TC, testosterone cypionate; BPH, benign prostatic hyperplasia; OSAS, obstructive sleep apnea syndrome; BA, controlled cohort before-and-after comparisons in the same group of patients; CBA, controlled before-and-after study between two or more groups of participants receiving different interventions.
Outcomes of the clinical studies included in the meta-analysis.
| Study (arm) (ref.) | Body weight | BMI | WC | Fat mass | Lean mass | Fasting glycemia | HOMA | Total cholesterol | HDL cholesterol | TG | Diastolic blood pressure | Systolic blood pressure |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| (27) | X | X | X | X | X | X | X | x | x | x | x | |
| (26) | X | X | X | X | x | x | ||||||
| (28) | X | X | X | X | X | X | X | x | x | x | x | |
| (29) | X | X | X | x | ||||||||
| (30) | X | X | X | |||||||||
| (86) | X | X | X | x | x | |||||||
| (31) | X | X | X | X | x | |||||||
| (87) | X | X | x | |||||||||
| (24) | X | X | X | |||||||||
| (32) | X | X | ||||||||||
| (88) | X | x | x | |||||||||
| (88)* | X | x | x | |||||||||
| (88)† | X | x | x | |||||||||
| (33) | X | X | X | X | X | x | x | |||||
| (25)‡ | X | X | X | X | x | |||||||
| (25)† | X | X | X | X | x | |||||||
| (89) | X | X | X | X | x | x | ||||||
| (90) | X | X | x | x | x | x | ||||||
| (91) | X | X | ||||||||||
| (34) | X | X | X | X | X | X | x | x | x | x | ||
| (92) | X | X | X | x | x | |||||||
| (35) | X | X | X | x | ||||||||
| (36) | X | X | X | X | ||||||||
| (93)‡ | X | X | ||||||||||
| (93)† | X | X | ||||||||||
| (94) | X | |||||||||||
| (37) | X | X | X | |||||||||
| (95) | X | X | ||||||||||
| (38) | X | X | X | X | x | |||||||
| (38)§ | X | X | X | X | x | |||||||
| (23) | X | X | X | |||||||||
| (96) | X | X | X | X | x | |||||||
| (39) | X | X | X | X | x | x | ||||||
| (40) | X | X | X | X | x | x | x | |||||
| (97) | X | X | X | X | X | X | X | x | x | x | x | |
| (98)§ | X | X | X | x | x | |||||||
| (98) | X | X | X | X | x | |||||||
| (99) | X | X | X | |||||||||
| (41) | X | X | X | |||||||||
| (100) | X | X | X | X | X | X | x | |||||
| (42) | X | X | X | X | X | X | X | X | X | x | ||
| (101) | X | X | X | X | X | X | X | x | ||||
| (102) | X | X | X | x | ||||||||
| (102)* | X | X | X | x | ||||||||
| (43) | X | X | X | X | X | X | X | X | X | x | ||
| (44) | X | X | X | X | X | X | x | x | x | |||
| (103) | X | X | X | X | x | x | x | |||||
| (104) | X | X | ||||||||||
| (105) | X | X | X | X | X | X | X | X | x | x | x | |
| (106) | X | X | X | X | X | X | X | X | x | x | x | |
| (107) | X | X | X | X | X | X | x | x | ||||
| (45) | X | X | X | X | X | X | X | x | ||||
| (108) | X | X | X | X | x | |||||||
| (109) | X | X | ||||||||||
| (110) | X | X | X | X | X | X | X | x | x | x | ||
| (111) | X | X | ||||||||||
| (46) | X | X | X | X | X | X | X | x | ||||
| (47) | X | X | X | |||||||||
| (48) | X | X | X | X | X | X | X | x | x | |||
| (49) | X | X | X | |||||||||
| (112) | X | X | ||||||||||
| (112)§ | X | X | ||||||||||
| (50) | X | X | X | X | X | X | X | x | x | x | ||
| (51)§ | X | X | X | X | ||||||||
| (51) | X | X | X | X | ||||||||
| (113) | X | X | X | X | X | x | x | x | ||||
| (22) | X | X | X | X | X | X | X | X | X | x | x | x |
| (52) | X | X | X | X | X | X | X | X | X | x | x | x |
Data on *T enathathe, †T pellet, ‡T gel, §T plus physical activity.
Characteristics and outcomes of the randomized clinical trials and observational studies included in the meta-analysis.
| Study (ref.) | Design | Blinding | Drop-out | Intention-to-treat | Eligibility criteria listed |
|---|---|---|---|---|---|
| (27) | Parallel | A | A | Yes | Yes |
| (26) | Cross-over | A | A | Yes | Yes |
| (28) | Parallel | A | A | Yes | Yes |
| (29) | NAP | NAP | A | Yes | Yes |
| (30) | NAP | NAP | NA | Yes | Yes |
| (86) | NAP | NAP | A | Yes | Yes |
| (31) | Parallel | NA | A | No | Yes |
| (87) | Parallel | NA | NA | Yes | Yes |
| (24) | Parallel | A | A | No | No |
| (32) | Parallel | A | NA | No | Yes |
| (88) | NAP | NAP | NA | No | Yes |
| (88)* | NAP | NAP | NA | No | Yes |
| (88)† | NAP | NAP | NA | No | Yes |
| (33) | Parallel | A | A | Yes | Yes |
| (25)‡ | NAP | NAP | A | No | Yes |
| (25)† | NAP | NAP | A | No | Yes |
| (89) | Parallel | A | A | Yes | Yes |
| (90) | Parallel | A | NA | No | Yes |
| (91) | Parallel | A | A | Yes | Yes |
| (34) | NAP | NAP | A | Yes | Yes |
| (92) | Parallel | A | A | Yes | Yes |
| (35) | Parallel | A | NA | No | Yes |
| (36) | Cross-over | A | A | Yes | Yes |
| (93)‡ | NAP | NAP | A | A | Yes |
| (93)† | NAP | NAP | A | A | Yes |
| (94) | Parallel | A | A | Yes | Yes |
| (37) | Parallel | NA | NA | No | Yes |
| (95) | Parallel | A | A | Yes | Yes |
| (38) | Parallel | A | A | Yes | Yes |
| (38)§ | Parallel | A | A | Yes | Yes |
| (23) | Parallel | A | A | No | No |
| (96) | NAP | NAP | NA | Yes | Yes |
| (39) | Parallel | A | A | Yes | Yes |
| (40) | Parallel | A | A | Yes | Yes |
| (97) | Cross-over | A | A | No | Yes |
| (98)§ | Parallel | A | A | Yes | Yes |
| (98) | Parallel | A | A | Yes | Yes |
| (99) | Parallel | A | NA | Yes | Yes |
| (41) | Cross-over | A | A | Yes | Yes |
| (100) | Parallel | A | A | No | Yes |
| (42) | Parallel | A | A | Yes | Yes |
| (101) | Parallel | A | A | Yes | Yes |
| (102) | NAP | NAP | A | Yes | Yes |
| (102)* | NAP | NAP | A | Yes | Yes |
| (43) | Parallel | A | A | No | Yes |
| (44) | Parallel | A | A | No | Yes |
| (103) | NAP | NAP | A | Yes | Yes |
| (114) | Parallel | A | NA | Yes | Yes |
| (105) | Parallel | A | NA | No | Yes |
| (106) | Parallel | A | NA | No | Yes |
| (107) | Cross-over | A | NA | No | Yes |
| (45) | Parallel | A | A | Yes | Yes |
| (108) | Parallel | A | A | Yes | Yes |
| (109) | Parallel | NA | A | Yes | Yes |
| (110) | Parallel | A | NA | Yes | Yes |
| (111) | Parallel | A | A | Yes | Yes |
| (46) | Parallel | A | NA | No | Yes |
| (47) | A | A | A | Yes | Yes |
| (48) | Parallel | A | A | Yes | Yes |
| (49) | Parallel | A | A | Yes | Yes |
| (112) | Parallel | A | NA | Yes | Yes |
| (112)§ | Parallel | A | NA | Yes | Yes |
| (50) | Parallel | A | A | A | Yes |
| (51)§ | Parallel | A | NA | Yes | Yes |
| (51) | Parallel | A | NA | Yes | Yes |
| (113) | Parallel | A | A | Yes | Yes |
| (22) | NAP | NAP | A | A | Yes |
| (52) | Parallel | A | A | A | Yes |
A, adequately described; NA, non-adequately described; NAP, not applicable. Data on *T enathathe, †T pellet, ‡T gel, §T plus physical activity.
Studies that met inclusion criteria but did not provide data for meta-analysis.
| References | Short summer of the study and main conclusions |
|---|---|
| (129) | With the aims of comparing the pharmacokinetics and pharmacodynamics of three different formulations of T, 15 hypogonadal men were studied. However, those results were not included in our meta-analysis since the group of participants consisted of not all naive patients |
| (130) | The study consisted in evaluating the TRT effects on serum lipids and lipoproteins in 13 hypogonadal men. This work was ruled out given that the patients group was made up of pre-pubertal and post-pubertal men |
| (131) | Controlled cohort study before and after comparison in the same group of constitutionally delayed puberty boys. TRT (TU 40 mg o.s.) increased fat free mass |
| (132) | A comparative study aims to verify the pharmacokinetics and bioefficacy of two doses of sublingual T cyclodextrin (2.5 and 5.0 mg; three times per day) with TE (once every 20 days) by i.m. injections over a 2 months study period in 63 hypogonadal men. However, the data could not employ as the group of participants were not all naïve subjects |
| (133) | The effects of gonadotropin and T therapies on lipids and lipoprotein(a) were studied in 31 hypogonadal males. The data were not considered for our study since the patients were pre-pubertal men |
| (134) | This study aims to look at the T role in developing insulin resistance and other cardiovascular risks factors in men. The data were not included in the meta analysis as were obtained from a group of subjects affected by puberty delayed |
| (135) | RCT on the effects of placebo or TE (25, 50, 125, 300 or 600 mg). Data on body composition were provided but the study was excluded since hypogonadism was artificially induced in healthy men by the use of GnRH agonist |
| (136) | Cross-over RCT of the effects of T patch (50 mg/day) and sildenafil for 8 weeks on sexual function in hypogonadal men with erectile dysfunction. The combined therapy with PDE5 and T or placebo can influence the outcomes of the study |
| (137) | Observational cohort study before and after study between two groups of participants receiving T (T cyprionate 200 mg/3 weeks) or not. There are not data about circulating T both in baseline and at the end of the study. In addition, the data are not complete |
| (138) | Observational cohort study before and after comparison in the same group of pre-pubertal hypogonadic men. TRT (T undercyclate 40 mg o.s.) increased weight and BMI. The data were not considered for our study since the patients were pre-pubertal boys |
| NCT00957528 | RCT on the effects of T (TE100 mg/week) on muscle strength and lean body mass. There are incomplete data and serum T at the start and the end of the study is not reported |
| (139) | RCT on the effects of placebo, T (gel 1.25, 2.5, 5 or 10 g) and anastrozole (to suppress the conversion of T to estradiol). Data on body composition were provided but the study was excluded since hypogonadism was artificially induced in healthy men by the use of GnRH agonist |
Outcome
The principal outcome of this analysis was the effect of TS, as compared with placebo or control group, on body composition modification including fat and lean mass. Secondary outcomes included several other glycometabolic parameters (Table 3).
Quality assessment
The quality of trials was assessed using the Cochrane criteria ((142); see also Table 4). In particular, the following criteria were evaluated: how the randomization sequence was generated, how allocation was concealed, whether there were important imbalances at baseline, which groups were blinded (patients, caregivers, data collectors, outcome assessors, data analysts), what the loss to follow-up rate was (in the intervention and the control arm), whether the analyses were by intention to treat and how missing outcome data were dealt with. For each study, we also assessed how the population was selected, the duration and route of TS, and the adequacy of study follow-up (143).
Statistical analysis
Heterogeneity was assessed by using I2 statistics. However, a random-effects model was applied for all analyses, even when low heterogeneity was detected, because the validity of tests of heterogeneity can be limited with a small number of component studies. To estimate possible publication or disclosure bias, we used funnel plots and the Begg adjusted rank correlation test (144, 145). However, because these tests have low statistical power when the number of trials is small, undetected bias may still be present. In addition, since in some trials the significance of between group comparisons (P) was not reported, the analysis was performed evaluating endpoint values of each parameter in different treatment groups, in a non-paired fashion (non-paired analysis). Considering that most of the studies, which did not describe P values, reported non-significant differences across groups, the mean (paired) analysis, which excludes those data, is likely to overestimate the effect of treatments. On the other hand, the non-paired analysis is a very conservative approach, which could underestimate treatment effect. Since body fat mass and lean mass were evaluated through different approaches and expressed in different ways, the mean difference for each study was divided by the pooled estimate of the SD, in order to express the effect size for each study in a common metric, namely the standardized mean difference (SMD). According to Cohen (145), a small treatment-effect size is considered to be about 0.2, a medium effect size to be about 0.5, and a large effect size to be about 0.8. All other data were expressed as weight mean differences. Meta-regression analyses were done in order to test the effects of final T plasma levels on fat and lean mass modification as well as on fasting glycaemia reduction only in placebo-controlled RCTs. Specific sensitivity analyses were also performed to evaluate the effects of the different T preparations on body composition and glycometabolic profile in placebo-controlled RCTs. Multivariate linear regression analysis model, weighing each study for the number of subjects enrolled, was performed in order to verify the effect of TS on fasting glycaemia and HOMA index after the adjustment for differences between the active arm and placebo in total T levels, fat and lean mass at end-point as a well as the mean age of the subjects enrolled and trial duration. In addition, other confounding factors such as BMI and prevalence of diabetes at baseline were considered. All analyses were performed using Comprehensive Meta-analysis Version 2, Biostat (Englewood, NJ, USA). Multivariate analyses were performed on SPSS (Statistical Package for the Social Sciences) for Windows 22.0.
Results
Out of 824 retrieved articles, 59 were included in the study (Fig. 1). Among them, 48 were placebo controlled. The characteristics of the retrieved trials (including parameters on trial quality) and type of outcomes considered are reported in Tables 2 and 3. Retrieved studies included 3029 and 2049 subjects in TS and control groups, respectively; mean trial duration was 8.7 months. TS was administered in different doses, formulations and cohorts (Table 2).
The mean age, baseline T and BMI of enrolled patients were 62.0 years, 11.6 nmol/l and 28.6 kg/m2 respectively.
T levels
Overall, the use of all T preparations resulted in significantly higher T levels when compared to control group (not shown). However, when only placebo-controlled RCTs were considered, parenteral preparations were associated with the highest T circulating levels at follow up when compared to those observed with oral and transdermal drugs (mean T differences vs placebo 7.69 (6.23; 9.14), 7.57 (5.72; 9.43) vs 2.39 (−0.43; 5.21) nM for parenteral, transdermal and oral preparations respectively; P<0.005 for oral in comparisons to parenteral and transdermal drugs). Conversely, no differences were observed when injectable TU formulation was compared to other parenteral preparations (not shown).
Body composition
Among studies reporting several outcomes, 32 included information on weight (Table 3). Funnel plot and Begg-adjusted rank correlation test suggested no small study effects (Kendall's τ: −0.10; P=0.38). TS was not associated with a reduction of body weight, WC and BMI (Fig. 2 and Supplementary Figure 1, see section on supplementary data given at the end of this article, panels A, B and C).
Weighted mean differences (with 95% CI) of body weight, WC, BMI, fat and lean mass, fasting glycaemia, HOMA index, total cholesterol, triglycerides, HDL-cholesterol, systolic (SBP) and diastolic (DBP) blood pressure at end point in studies enclosed in the analysis. *Standardized means were considered.
Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0262
Weighted mean differences (with 95% CI) of body weight, WC, BMI, fat and lean mass, fasting glycaemia, HOMA index, total cholesterol, triglycerides, HDL-cholesterol, systolic (SBP) and diastolic (DBP) blood pressure at end point in studies enclosed in the analysis. *Standardized means were considered.
Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0262
Weighted mean differences (with 95% CI) of body weight, WC, BMI, fat and lean mass, fasting glycaemia, HOMA index, total cholesterol, triglycerides, HDL-cholesterol, systolic (SBP) and diastolic (DBP) blood pressure at end point in studies enclosed in the analysis. *Standardized means were considered.
Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0262
Information on fat mass and lean mass were available from 42 and 40 studies, respectively (Table 3). TS was associated with a significant reduction of fat and with an increase of lean mass (Fig. 2, and Supplementary Figure 1, see section on supplementary data given at the end of this article, panels D and E). These effects were confirmed even when only trials using DEXA-derived data were considered (standardized means −0.34 (−0.48; −0.20) and 0.55 (0.39; 0.72) for fat and lean mass respectively; both P<0.0001). Similar results were observed when only placebo-controlled RCTs were considered (standardized means −0.36 (−0.51; −0.20) and 0.57 (0.38; 0.75) for fat and lean mass respectively; both P<0.0001) or after excluding those trials enrolling mixed (eugonadal and hypogonadal) populations (standardized means −0.39 (−0.61; −0.17) and 0.45 (0.26; 0.63) for fat and lean mass, respectively; both P<0.0001).
By performing a sensitivity analysis on only placebo-controlled RCTs, no relationship between fat and lean mass modification, and final levels of T was detected at meta-regression analysis (not shown). However, when the data were analysed according to the type of T preparation used, no improvement in body composition (both lean and fat mass modification) was observed in those trials using oral T preparations (SMD −e−0.61; 0.04); P=0.08 and 1.59 (−0.64; 3.83); P=0.16 for fat and lean mass respectively). Conversely, the use of both transdermal and parenteral preparations significantly improved body composition with the use of the latter dugs resulting in better outcomes (mean standardized difference −0.67 (−1.01; −0.33) vs −0.16 (−0.31; −0.01); Q=7.19, P< 0.01 and 0.61 (0.37; 0.85) vs 0.33 (0.18; 0.47); Q=3.80, P=0.05 for fat mass and lean mass, respectively). In addition, among parenteral preparations, injectable TU produced better results when compared to other parenteral formulations (mean standardized difference −0.93 (−1.76; −0.09) vs −0.53 (−0.82; −0.24); Q=7.55, P=0.023 and 0.87 (0.62; 1.11) vs 0.42 (0.07; 0.77); Q=13.9, P=0.001 for fat mass and lean mass respectively).
Glyco-metabolic profile and blood pressure
TS was associated with a reduction of fasting glycaemia and insulin resistance (IR), as detected by HOMA-IR index (Fig. 2, see also Supplementary Figure 1, see section on supplementary data given at the end of this article, panels F and G). Similar results were observed when only placebo-controlled RCTs were considered (standardized means −0.28 (−0.45; −0.12) and −0.72 (−1.11; −0.33) for glycaemia and HOMA index respectively; both P<0.001) or after excluding those trials enrolling mixed (eugonadal and hypogonadal) populations (standardized means −0.37 (−0.65; -0.09) and −1.27 (−1.84; −0.71) for glycaemia and HOMA index, respectively; both P<0.01).
By performing a further sensitivity analysis on only placebo-controlled trials, no relationship between glucose level modification and final levels of T was detected at meta-regression analysis (not shown). However, when the data were analysed according to the type of T preparation used, no improvement in glucose levels was observed in those trials using oral T preparations (mean difference −0.77 (−1.87; 0.33); P=0.17). Conversely, the use of both transdermal and parenteral preparations significantly improved fasting glycaemia with the use of the latter drugs resulting in better outcomes (mean difference −0.48 (−0.64; −0.32) vs −0.23 (−0.37; −0.10); Q=5.95, P=0.015).
In order to verify whether the glycaemic effects of TS could be associated with a variation in body composition, a multivariate linear regression analysis was performed weighting each study for the number of subjects enrolled, by introducing in the same model, differences between the active arm and placebo in total T levels, fat and lean mass at end-point, age and trial duration as possible predictors of differences in fasting glycaemia and HOMA-IR index. The results of this analysis are reported in Table 6. Between-group differences in fasting glycaemia and HOMA-IR index were related to modification in lean but not in fat mass (Table 6). The association with lean mass was confirmed in alternative multivariate regression models when other confounding factors such as BMI (adj r=0.32 and 0.35 for fasting glycaemia and HOMA index respectively; both P<0.0001) and prevalence of diabetes (adj. r=0.32 and 0.46 for fasting glycaemia and HOMA index respectively; both P<0.0001) at baseline were considered.
End-point T level modification adjusted relationship between TS-induced glycol-metabolic improvement and body composition changes. Data are derived from a multivariate linear regression model, weighting each study for the number of subjects enrolled, introducing the differences between the active arm and placebo in total T levels and fat and lean mass at end-point as well as age and trial duration as possible predictors of differences in fasting glycaemia and HOMA-IR index.
| Lean mass | Fat mass | |||
|---|---|---|---|---|
| Adj. R | P | Adj. r | P | |
| HOMA index | 0.82 | 0.001 | −0.02 | 0.43 |
| Fasting glycaemia | 0.48 | 0.001 | −0.05 | 0.27 |
When lipid profile was analysed, no effect of TS on total cholesterol as well as triglyceride levels was observed (Fig. 2, see also Supplementary Figure 1, see section on supplementary data given at the end of this article, panels H and I). However, when only placebo-controlled trials enrolling hypogonadal (TT <12 nmol/l) subjects at baseline were considered, a positive effect of TS on total cholesterol (−0.35 (−0.61; −0.08) mM; P<0.0001) and triglyceride (−0.22 (−0.37; 0.08) mM; P=0.003) reduction was observed. Conversely, no effect of TS in HDL cholesterol levels as well as in both systolic and diastolic blood pressure was observed (Fig. 2, and Supplementary Figure 1, see section on supplementary data given at the end of this article, panel L and N). Similar results were observed when only placebo-controlled RCTs were considered (−0.23 (−0.37; −0.10) and −0.09 (−0.14; −0.03) for total cholesterol and triglycerides respectively; both P<0.005) or after excluding those trials enrolling mixed (eugonadal and hypogonadal) populations (−0.28 (−0.44; −0.12) and −0.18 (−0.33; −0.04) for total cholesterol and triglycerides respectively; both P<0.05).
Sensitivity analysis according to population characteristics at baseline in placebo controlled RCTs
No difference in T levels at end point was observed by comparing obese (BMI ≥30 kg/m2; n=11) and non-obese subjects (n=21) at baseline (8.24 (5.64; 10.85) vs 6.84 (5.59; 8.08), Q=0.91, P=0.34).
TS produced better outcomes in reducing fat mass in hypogonadal (total T <12 nM) subjects at baseline when compared to the rest of the sample (−0.67 (−1.07; −0.27) vs -0.23 (−0.38; −0.08); Q=4.12; P=0.04). Conversely, no difference in lean mass between hypogonadal or not hypogonadal patients at baseline was observed (0.54 (0.32; 0.76) vs 0.65 (0.29; 1.01); Q=0.27, P=0.60).
Furthermore, by comparing the effect of TS in subjects with a metabolic disease (n=11) to those evaluating elderly men (n=10), the improvement of fasting glycaemia was even higher in the former group when compared to the latter (−0.52 (−0.78; −0,25) vs 0.19 (−0.34; −0.04) mM; Q=4.22, P=0.03). Accordingly, the effect of TS was higher in obese subjects (BMI >30 kg/m2) when compared to the rest of the sample (mean difference vs placebo −0.49 (−0.69; −0.30) vs −0.25 (−0.38; −0.11) mM; Q=4.13, P=0.04). In addition, a better outcome was also observed in younger individuals (the median age <60 years; −0.52 (−0.65; −0.39) vs −0.14 (−0.28; 0.01) mM; Q=14.65 P<0.0001).
Discussion
The present meta-analysis indicates that TS in men – heterogeneous in terms of BMI and metabolic conditions – is associated, in controlled studies, with a small to medium pooled effect size reduction of total fat and an increase in lean mass that is exactly of the same order of magnitude, although in the opposite direction (0.3 and 0.5 SMD respectively). A previous meta-analysis, involving half of the studies scrutinized here (74), reported similar results. The dual, opposite effects of TS on body composition, i.e. an increase in lean mass and a reduction in fat mass, might justify the overall null efficacy of TS on body weight or BMI. Present results are in apparent contrast with several observational studies indicating that TS is associated with a significant weight loss (62, 64, 65, 66, 67, 68, 69) and decrease in BMI (64, 66, 68, 69, 126, 128) and WC (60, 64, 66, 67, 68, 69, 113, 123, 128). RCTs and observational studies obviously differ in study design and patient allocation criteria. However, as far as the effect of TS on obesity is concerned, they also differ in baseline T level and follow-up duration. In particular, in observational studies, the subjects usually enrolled had more severe hypogonadism and were followed for a longer period. Different patient medication adherence might further contribute to the differences in effects observed. It is important to note that diagnosis of hypogonadism allows only for a short period of placebo-controlled design because the condition is associated with an increased risk of osteoporosis or other metabolic and sexual side effects. Hence, long-term, placebo-controlled studies are scarcely feasible.
TS, even in men with LOH, cannot be considered as a true short-term anti-obesity medication (17), because its effect on body weight is not apparent, at least in the timeframe covered by RCTs.
However, our data showed that TS is not only associated with an improvement in body composition, but also with a more favourable glycometabolic profile. Here we reported a small but significant effect of active treatment on glycaemia and insulin sensitivity, as detected by HOMA-IR index. Similar results were previously reported in selected LOH populations, such as T2DM and MetS (15, 78, 79, 80, 81). It is conceivable that the improvement in glucose metabolism can be ascribed to increased muscle mass or to decreased fat mass. In an experimental model of MetS-associated hypogonadism, obtained by feeding rabbits a high-fat diet, we demonstrated that T administration was able to dramatically reduce visceral adiposity and, in cultured adipocytes, to increase insulin sensitivity and triglyceride metabolism (146). It is interesting to note that the positive associations among T levels, glycaemia and HOMA-IR index were not confirmed in a multivariate model after adjusting for lean, but not fat and mass. This suggests that increased muscle mass is somehow responsible for the more favourable glucose metabolism associated with TS. None of the known anti-obesity medications or surgical interventions improve muscle mass in the way that has been observed with TS.
Positive changes in lipid profile were seen in RCTs considering patients with hypogonadism, but not in eugonadal/mixed subjects. Our results are essentially in agreement with those from some of the previous meta-analyses (73, 74).
The effects of any treatment obviously depend on the characteristics of the subjects receiving that treatment. With respect to its metabolic effects, TS seems to be more effective in younger men and in those with metabolic disturbances. This finding could be of help in defining the population that could benefit most from TS.
Given that in the general European population more than 40 and 25% of obese individuals (BMI ≥30 kg/m2) have total T below 12 or 10.4 nmol/l, respectively (19), results of the present meta-analysis are relevant. In fact, TS in these individuals might help them in changing body composition and glucose metabolism. However, the present meta-analysis shows several limitations. In fact, the RCTs scrutinized here were neither specifically designed for weight loss nor had obesity as a selection criterion. In addition, enrolled subjects were not wishing to lose weight. It is possible that motivated, obese, hypogonadal subjects will respond differently to active treatment. Furthermore, it is conceivable that increased muscle mass will allow obese individuals to adhere to structured lifestyle interventions, which include physical activity. All these points should be addressed by dedicated clinical trials.
In conclusion, the present meta-analysis suggests that TS is able to improve body composition and glycometabolic profile particularly in younger subjects and in those with metabolic disturbances even though an overt effect on WC and/or body weight is not apparent. Specifically designed studies are urgently needed to confirm this point.
Supplementary data
This is linked to the online version of the paper at http://dx.doi.org/10.1530/EJE-15-0262.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
References
- 1↑
World Health Organization. Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva: World Health Organization, 2009
- 2↑
Corona G, Monami M, Boddi V, Balzi D, Melani C, Federico N, Balzi D, Sforza A, Rotella CM, Forti G et al.. Is obesity a further cardiovascular risk factor in patients with erectile dysfunction? Journal of Sexual Medicine 2010 7 2538–2546. (doi:10.1111/j.1743-6109.2010.01839.x).
- 3↑
Corona G, Rastrelli G, Filippi S, Vignozzi L, Mannucci E, Maggi M. Erectile dysfunction and central obesity: an Italian perspective. Asian Journal of Andrology 2014 16 581–591. (doi:10.4103/1008-682X.126386).
- 4↑
Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L et al.. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case–control study. Lancet 2005 366 1640–1649. (doi:10.1016/S0140-6736(05)67663-5).
- 5↑
Corona G, Rastrelli G, Morelli A, Vignozzi L, Mannucci E, Maggi M. Hypogonadism and metabolic syndrome. Journal of Endocrinological Investigation 2011 34 557–567. (doi:10.1007/BF03347072).
- 6↑
Shaw K, O'Rourke P, Del Mar C, Kenardy J. Psychological interventions for overweight or obesity. Cochrane Database of Systematic Reviews 2005 CD003818.
- 7↑
Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L, NN8022-1923 Investigators . Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. International Journal of Obesity 2013 37 1443–1451. (doi:10.1038/ijo.2013.120).
- 8↑
Middleton KM, Patidar SM, Perri MG. The impact of extended care on the long-term maintenance of weight loss: a systematic review and meta-analysis. Obesity Reviews 2012 13 509–517. (doi:10.1111/j.1467-789X.2011.00972.x).
- 9↑
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. Journal of the American Medical Association 2014 311 74–86. (doi:10.1001/jama.2013.281361).
- 10↑
Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG et al.. Meta-analysis: pharmacologic treatment of obesity. Annals of Internal Medicine 2005 142 532–546. (doi:10.7326/0003-4819-142-7-200504050-00012).
- 11↑
Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME, NN8022-1807 Study Group . Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009 374 1606–1616. (doi:10.1016/S0140-6736(09)61375-1).
- 12↑
Peirson L, Douketis J, Ciliska D, Fitzpatrick-Lewis D, Ali MU, Raina P. Treatment for overweight and obesity in adult populations: a systematic review and meta-analysis. CMAJ Open 2014 2 E306–E317. (doi:10.9778/cmajo.20140012).
- 13↑
Ross R, Shaw KD, Rissanen J, Martel Y, de Guise J, Avruch L. Sex differences in lean and adipose tissue distribution by magnetic resonance imaging: anthropometric relationships. American Journal of Clinical Nutrition 1994 59 1277–1285.
- 14↑
Lee JJ, Beretvas SN, Freeland-Graves JH. Abdominal adiposity distribution in diabetic/prediabetic and non diabetic populations: a meta-analysis. Journal of Obesity 2014 2014 697264. (doi:10.1155/2014/697264).
- 15↑
Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Practice & Research. Clinical Endocrinology & Metabolism 2013 27 557–579. (doi:10.1016/j.beem.2013.05.002).
- 16↑
Corona G, Rastrelli G, Vignozzi L, Mannucci E, Maggi M. How to recognize late-onset hypogonadism in men with sexual dysfunction. Asian Journal of Andrology 2012 14 251–259. (doi:10.1038/aja.2011.138).
- 17↑
Saad F, Aversa A, Isidori AM, Gooren LJ. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Current Diabetes Reviews 2012 8 131–143. (doi:10.2174/157339912799424573).
- 18↑
Corona G, Rastrelli G, Monami M, Saad F, Luconi M, Lucchese M, Facchiano E, Sforza A, Forti G, Mannucci E et al.. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. European Journal of Endocrinology 2013 168 829–843. (doi:10.1530/EJE-12-0955).
- 19↑
Tajar A, Huhtaniemi IT, O'Neill TW, Finn JD, Pye SR, Lee DM, Bartfai G, Boonen S, Casanueva FF, Forti G et al.. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). Journal of Clinical Endocrinology and Metabolism 2012 97 1508–1516. (doi:10.1210/jc.2011-2513).
- 20↑
Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with 'diabesity': results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. International Journal of Endocrinology 2014 2014 683515.
- 21↑
Neff KJ, le Roux CW. Bariatric surgery: a best practice article. Journal of Clinical Pathology 2013 66 90–98. (doi:10.1136/jclinpath-2012-200798).
- 22↑
Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. Journal of Endocrinological Investigation 2014 37 401–411. (doi:10.1007/s40618-014-0066-9).
- 23↑
Svartberg J, Aasebø U, Hjalmarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respiratory Medicine 2004 98 906–913. (doi:10.1016/j.rmed.2004.02.015).
- 24↑
Clague JE, Wu FC, Horan MA. Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men. International Journal of Andrology 1999 22 261–265. (doi:10.1046/j.1365-2605.1999.00177.x).
- 25↑
Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N, Testosterone Gel Study Group . Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 2000 85 2839–2853.
- 26↑
Tenover JS. Effects of testosterone supplementation in the aging male. Journal of Clinical Endocrinology and Metabolism 1992 75 1092–1098.
- 27↑
Mårin P, Holmäng S, Jönsson L, Sjöström L, Kvist H, Holm G, Lindstedt G, Björntorp P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. International Journal of Obesity and Related Metabolic Disorders 1992 16 991–997.
- 28↑
Mårin P, Holmäng S, Gustafsson C, Jönsson L, Kvist H, Elander A, Eldh J, Sjöström L, Holm G, Björntorp P. Androgen treatment of abdominally obese men. Obesity Research 1993 1 245–251.
- 29↑
Morley JE, Perry HM III, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM Jr. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. Journal of the American Geriatrics Society 1993 41 149–152. (doi:10.1111/j.1532-5415.1993.tb02049.x).
- 30↑
Young NR, Baker HW, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. Journal of Clinical Endocrinology and Metabolism 1993 77 1028–1032.
- 31↑
Sih R, Morley JE, Kaiser FE, Perry HM III, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. Journal of Clinical Endocrinology and Metabolism 1997 82 1661–1667. (doi:10.1210/jcem.82.6.3988).
- 32↑
Giorgi A, Weatherby RP, Murphy PW. Muscular strength, body composition and health responses to the use of testosterone enanthate: a double blind study. Journal of Science and Medicine in Sport 1999 2 341–355. (doi:10.1016/S1440-2440(99)80007-3).
- 33↑
Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ et al.. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. Journal of Clinical Endocrinology and Metabolism 1999 84 2647–2653.
- 34↑
Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003 6 1–7. (doi:10.1080/tam.6.1.1.7).
- 35↑
Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Urban RJ, Wolfe RR. Differential anabolic effects of testosterone and amino acid feeding in older men. Journal of Clinical Endocrinology and Metabolism 2003 88 358–362. (doi:10.1210/jc.2002-021041).
- 36↑
Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR, Handelsman DJ. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. Journal of Clinical Endocrinology and Metabolism 2003 88 3605–3613. (doi:10.1210/jc.2003-030236).
- 37↑
Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R, North American AA2500 T Gel Study Group . AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. Journal of Clinical Endocrinology and Metabolism 2003 88 2673–2681. (doi:10.1210/jc.2002-021058).
- 38↑
Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, Fournier M, Storer TW. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2004 170 870–878. (doi:10.1164/rccm.200305-617OC).
- 39↑
Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. Journal of Clinical Endocrinology and Metabolism 2005 90 1502–1510. (doi:10.1210/jc.2004-1933).
- 40↑
Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, Whyte M, McMillan CV, Bradley C, Martin FC. The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. Journal of Clinical Endocrinology and Metabolism 2006 91 477–484. (doi:10.1210/jc.2005-0957).
- 41↑
Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. European Journal of Heart Failure 2007 9 44–50. (doi:10.1016/j.ejheart.2006.04.006).
- 42↑
Allan CA, Strauss BJ, Burger HG, Forbes EA, McLachlan RI. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in non obese aging men. Journal of Clinical Endocrinology and Metabolism 2008 93 139–146. (doi:10.1210/jc.2007-1291).
- 43↑
Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. International Journal of Impotence Research 2008 20 378–387. (doi:10.1038/ijir.2008.19).
- 44↑
Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. Journal of the American College of Cardiology 2009 54 919–927. (doi:10.1016/j.jacc.2009.04.078).
- 45↑
Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clinical Endocrinology 2010 73 602–612. (doi:10.1111/j.1365-2265.2010.03845.x).
- 46↑
Sheffield-Moore M, Dillon EL, Casperson SL, Gilkison CR, Paddon-Jones D, Durham WJ, Grady JJ, Urban RJ. A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. Journal of Clinical Endocrinology and Metabolism 2011 96 E1831–E1837. (doi:10.1210/jc.2011-1262).
- 47↑
Frederiksen L, Højlund K, Hougaard DM, Mosbech TH, Larsen R, Flyvbjerg A, Frystyk J, Brixen K, Andersen M. Testosterone therapy decreases subcutaneous fat and adiponectin in aging men. European Journal of Endocrinology 2012 166 469–476. (doi:10.1530/EJE-11-0565).
- 48↑
Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. European Journal of Endocrinology 2012 167 531–541. (doi:10.1530/EJE-12-0525).
- 49↑
Bouloux PM, Legros JJ, Elbers JM, Geurts TB, Kaspers MJ, Meehan AG, Meuleman EJ, Study 43203 Investigators . Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: a 1-year, randomized, placebo-controlled, dose-ranging study. Aging Male 2013 16 38–47. (doi:10.3109/13685538.2013.773420).
- 50↑
Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. Journal of Sexual Medicine 2013 10 1612–1627. (doi:10.1111/jsm.12146).
- 51↑
Hildreth KL, Barry DW, Moreau KL, Vande Griend J, Meacham RB, Nakamura T, Wolfe P, Kohrt WM, Ruscin JM, Kittelson J et al.. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. Journal of Clinical Endocrinology and Metabolism 2013 98 1891–1900. (doi:10.1210/jc.2012-3695).
- 52↑
Gianatti EJ, Dupuis P, Hoermann R, Strauss BJ, Wentworth JM, Zajac JD, Grossmann M. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care 2014 37 2098–2107. (doi:10.2337/dc13-2845).
- 53↑
Valdemarsson S, Hedner P, Nilsson-Ehle P. Increase in hepatic lipase activity after testosterone substitution in men with hypogonadism of pituitary origin. Acta Medica Scandinavica 1987 221 363–366. (doi:10.1111/j.0954-6820.1987.tb03357.x).
- 54↑
Mårin P, Krotkiewski M, Björntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissues. European Journal of Medicine 1992 1 329–336.
- 55↑
Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men – a clinical research center study. Journal of Clinical Endocrinology and Metabolism 1996 81 3469–3475.
- 56↑
Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. Journal of Clinical Endocrinology and Metabolism 1996 81 4358–4365.
- 57↑
Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley RE, Berman N, Davidson T et al.. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men – a clinical research center study. Journal of Clinical Endocrinology and Metabolism 1996 81 3654–3662.
- 58↑
Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 1997 82 407–413.
- 59↑
Naharci MI, Pinar M, Bolu E, Olgun A. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocrine Practice 2007 13 629–635. (doi:10.4158/EP.13.6.629).
- 60↑
Saad F, Gooren L, Haider A, Yassin A. An exploratory study of the effects of 12 month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Archives of Andrology 2007 53 353–357. (doi:10.1080/01485010701730880).
- 61↑
Saad F, Gooren LJ, Haider A, Yassin A. A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. Journal of Andrology 2008 29 102–105. (doi:10.2164/jandrol.107.002774).
- 62↑
Schwarz ER, Willix RD Jr. Impact of a physician-supervised exercise-nutrition program with testosterone substitution in partial androgen-deficient middle-aged obese men. Journal of Geriatric Cardiology 2011 8 201–206. (doi:10.3724/SP.J.1263.2011.00201).
- 63↑
Jo DG, Lee HS, Joo YM, Seo JT. Effect of testosterone replacement therapy on bone mineral density in patients with Klinefelter syndrome. Yonsei Medical Journal 2013 54 1331–1335. (doi:10.3349/ymj.2013.54.6.1331).
- 64↑
Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity 2013 21 1975–1981. 2. (doi:10.1002/oby.20407).
- 65↑
Tirabassi G, DelliMuti N, Corona G, Maggi M, Balercia G. Androgen receptor gene CAG repeat polymorphism regulates the metabolic effects of testosterone replacement therapy in male postsurgical hypogonadotropic hypogonadism. International Journal of Endocrinology 2013 2013 816740. (doi:10.1155/2013/816740).
- 66↑
Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. Journal of Sexual Medicine 2013 10 579–588. (doi:10.1111/j.1743-6109.2012.02853.x).
- 67↑
Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. International Journal of Endocrinology 2014 2014 527470. (doi:10.1155/2014/527470).
- 68↑
Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. Journal of Sexual Medicine 2014 11 1567–1576. (doi:10.1111/jsm.12523).
- 69↑
Zitzmann M, Saad F, Kliesch S. Long-term treatment with testosterone undecanoate injections leads to sustained weight loss and improvement of metabolic syndrome parameters in 381 hypogonadal men. Journal of Sexual Medicine 2014 11 (Suppl 1) 7.
- 70↑
Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clinical Obesity 2013 3 73–83. (doi:10.1111/cob.12022).
- 71↑
Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. Obesity Research & Clinical Practice 2014 8 e339–e349. (doi:10.1016/j.orcp.2013.10.005).
- 72↑
Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. International Journal of Clinical Practice 2014 68 314–329. (doi:10.1111/ijcp.12319).
- 73↑
Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. American Journal of Medicine 2001 111 261–269. (doi:10.1016/S0002-9343(01)00833-6).
- 74↑
Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clinical Endocrinology 2005 63 280–293. (doi:10.1111/j.1365-2265.2005.02339.x).
- 75↑
Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proceedings 2007 82 29–39. (doi:10.1016/S0025-6196(11)60964-6).
- 76↑
Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT et al.. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism 2010 95 2560–2575. (doi:10.1210/jc.2009-2575).
- 77↑
Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2005 60 1451–1457. (doi:10.1093/gerona/60.11.1451).
- 78↑
Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian Journal of Andrology 2014 16 146–152. (doi:10.4103/1008-682X.122346).
- 79↑
Corona G, Monami M, Rastrelli G, Aversa A, Sforza A, Lenzi A, Forti G, Mannucci E, Maggi M. Type 2 diabetes mellitus and testosterone: a meta-analysis study. International Journal of Andrology 2011 34 528–540. (doi:10.1111/j.1365-2605.2010.01117.x).
- 80↑
Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, Maggi M. Testosterone and metabolic syndrome: a meta-analysis study. Journal of Sexual Medicine 2011 8 272–283. (doi:10.1111/j.1743-6109.2010.01991.x).
- 81↑
Grossmann M, Hoermann R, Wittert G, Yeap BB. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clinical Endocrinology 2015 83 344–351. (doi:10.1111/cen.12664).
- 82↑
Johns K, Beddall MJ, Corrin RC. Anabolic steroids for the treatment of weight loss in HIV-infected individuals. Cochrane Database of Systematic Reviews 4 2005 CD005483.
- 83↑
Kong A, Edmonds P. Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis. Lancet. Infectious Diseases 2002 2 692–699. (doi:10.1016/S1473-3099(02)00441-3).
- 84↑
Atlantis E, Fahey P, Cochrane B, Wittert G, Smith S. Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. BMJ Open 2013 3 e003127. (doi:10.1136/bmjopen-2013-003127).
- 86↑
Reid IR, Wattie DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated men. Archives of Internal Medicine 1996 156 1173–1177. (doi:10.1001/archinte.1996.00440100065008).
- 87↑
Uyanik BS, Ari Z, Gümüs B, Yiğitoğlu MR, Arslan T. Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study. Japanese Heart Journal 1997 38 73–82. (doi:10.1536/ihj.38.73).
- 88↑
Jockenhövel F, Bullmann C, Schubert M, Vogel E, Reinhardt W, Reinwein D, Müller-Wieland D, Krone W. Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men. Metabolism 1999 48 590–596.
- 89↑
Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2001 56 M266–M272. (doi:10.1093/gerona/56.5.M266).
- 90↑
Simon D, Charles MA, Lahlou N, Nahoul K, Oppert JM, Gouault-Heilmann M, Lemort N, Thibult N, Joubert E, Balkau B et al.. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care 2001 24 2149–2151. (doi:10.2337/diacare.24.12.2149).
- 91↑
Blackman MR, Sorkin JD, Münzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O'Connor KG, Christmas C, Tobin JD et al.. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. Journal of the American Medical Association 2002 288 2282–2292. (doi:10.1001/jama.288.18.2282).
- 92↑
Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. Journal of Clinical Endocrinology and Metabolism 2003 88 3167–3176. (doi:10.1210/jc.2002-021827).
- 93↑
McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU International 2003 91 69–74. (doi:10.1046/j.1464-410X.2003.04016.x).
- 94↑
Park NC, Yan BQ, Chung JM, Lee KM. Oral testosterone undecanoate (Andriol) supplement therapy improves the quality of life for men with testosterone deficiency. Aging Male 2003 6 86–93. (doi:10.1080/tam.6.2.86.93).
- 95↑
Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2003 58 618–625. (doi:10.1093/gerona/58.7.M618).
- 96↑
Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 2004 89 2085–2098. (doi:10.1210/jc.2003-032006).
- 97↑
Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. European Journal of Endocrinology 2006 154 899–906. (doi:10.1530/eje.1.02166).
- 98↑
Katznelson L, Robinson MW, Coyle CL, Lee H, Farrell CE. Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men. European Journal of Endocrinology 2006 155 867–875. (doi:10.1530/eje.1.02291).
- 99↑
Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R et al.. DHEA in elderly women and DHEA or testosterone in elderly men. New England Journal of Medicine 2006 355 1647–1659. (doi:10.1056/NEJMoa054629).
- 100↑
Agledahl I, Hansen JB, Svartberg J. Impact of testosterone treatment on postprandial triglyceride metabolism in elderly men with subnormal testosterone levels. Scandinavian Journal of Clinical and Laboratory Investigation 2008 68 641–648. (doi:10.1080/00365510801999068).
- 101↑
Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. Journal of the American Medical Association 2008 299 39–52. (doi:10.1001/jama.2007.51).
- 102↑
Minnemann T, Schubert M, Freude S, Hübler D, Gouni-Berthold I, Schumann C, Christoph A, Oettel M, Ernst M, Mellinger U et al.. Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism. Journal of Endocrinological Investigation 2008 31 718–723. (doi:10.1007/BF03346421).
- 103↑
Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. Journal of Andrology 2009 30 726–733. (doi:10.2164/jandrol.108.007005).
- 104↑
Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. European Journal of Endocrinology 2009 161 443–449. (doi:10.1530/EJE-09-0092).
- 105↑
Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. Journal of Endocrinological Investigation 2010 33 776–783. (doi:10.1007/BF03350341).
- 106↑
Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, Spera G. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. Journal of Sexual Medicine 2010 7 3495–3503. (doi:10.1111/j.1743-6109.2010.01931.x).
- 107↑
Gopal RA, Bothra N, Acharya SV, Ganesh HK, Bandgar TR, Menon PS, Shah NS. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocrine Practice 2010 16 570–576. (doi:10.4158/EP09355.OR).
- 108↑
Kenny AM, Kleppinger A, Annis K, Rathier M, Browner B, Judge JO, McGee D. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. Journal of the American Geriatrics Society 2010 58 1134–1143. (doi:10.1111/j.1532-5415.2010.02865.x).
- 109↑
Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FC. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 2010 95 639–650. (doi:10.1210/jc.2009-1251).
- 110↑
Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD et al.. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011 34 828–837. (doi:10.2337/dc10-1233).
- 111↑
O'Connell MD, Roberts SA, Srinivas-Shankar U, Tajar A, Connolly MJ, Adams JE, Oldham JA, Wu FC. Do the effects of testosterone on muscle strength, physical function, body composition, and quality of life persist six months after treatment in intermediate-frail and frail elderly men? Journal of Clinical Endocrinology and Metabolism 2011 9 454–458. (doi:10.1210/jc.2010-1167).
- 112↑
Glintborg D, Christensen LL, Kvorning T, Larsen R, Brixen K, Hougaard DM, Richelsen B, Bruun JM, Andersen M. Strength training and testosterone treatment have opposing effects on migration inhibitor factor levels in ageing men. Mediators of Inflammation 2013 2013 539156. (doi:10.1155/2013/539156).
- 113↑
Tan WS, Low WY, Ng CJ, Tan WK, Tong SF, Ho C, Khoo EM, Lee G, Lee BC, Lee V et al.. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU International 2013 111 1130–1140. (doi:10.1111/bju.12037).
- 114↑
Garcia JA, Sanchez PE, Fraile C, Escovar P. Testosterone undecanoate improves erectile dysfunction in hypogonadal men with the metabolic syndrome refractory to treatment with phosphodiesterase type 5 inhibitors alone. Andrologia 2011 43 293–296. (doi:10.1111/j.1439-0272.2009.00991.x).
- 115↑
Rebuffé-Scrive M, Mårin P, Björntorp P. Effect of testosterone on abdominal adipose tissue in men. International Journal of Obesity 1991 15 791–795.
- 116↑
Forbes GB, Porta CR, Herr BE, Griggs RC. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. Journal of the American Medical Association 1992 267 397–399. (doi:10.1001/jama.1992.03480030075040).
- 117↑
Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 1996 121 35–43. (doi:10.1016/0021-9150(95)05673-4).
- 118↑
Tan KC, Shiu SW, Pang RW, Kung AW. Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins. Clinical Endocrinology 1998 48 187–194. (doi:10.1046/j.1365-2265.1998.3721211.x).
- 119↑
Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, Urban RJ, Veldhuis JD. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. Journal of Clinical Endocrinology and Metabolism 2002 87 5649–5657. (doi:10.1210/jc.2002-020098).
- 120↑
Minnemann T, Schubert M, Hübler D, Gouni-Berthold I, Freude S, Schumann C, Oettel M, Ernst M, Mellinger U, Sommer F et al.. four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate. Aging Male 2007 10 155–158. (doi:10.1080/13685530701437510).
- 121↑
La Vignera S, Calogero AE, Condorelli R, Lanzafame F, Giammusso B, Vicari E. Andrological characterization of the patient with diabetes mellitus. Minerva Endocrinologica 2009 34 1–9.
- 122↑
Moon du G, Park MG, Lee SW, Park K, Park JK, Kim SW, Park NC, Ahn TY, Paick JS, Seo JT et al.. The efficacy and safety of testosterone undecanoate (Nebido(®)) in testosterone deficiency syndrome in Korean: a multicentre prospective study. Journal of Sexual Medicine 2010 7 2253–2260. (doi:10.1111/j.1743-6109.2010.01765.x).
- 123↑
Permpongkosol S, Tantirangsee N. Ratana-olarnK.Treatment of 161 men with symptomatic late onset hypogonadism with long-acting parenteral testosterone undecanoate: effects on body composition, lipids, and psychosexual complaints. Journal of Sexual Medicine 2010 7 3765–3774. (doi:10.1111/j.1743-6109.2010.01994.x).
- 124↑
Arafa M, Zohdy W, Aboulsoud S, Shamloul R. Prevalence of late-onset hypogonadism in men with type 2 diabetes mellitus. Andrologia 2012 44 (Suppl 1) 756–763. (doi:10.1111/j.1439-0272.2011.01262.x).
- 125↑
Schroeder ET, He J, Yarasheski KE, Binder EF, Castaneda-Sceppa C, Bhasin S, Dieli-Conwright CM, Kawakubo M, Roubenoff R, Azen SP et al.. Value of measuring muscle performance to assess changes in lean mass with testosterone and growth hormone supplementation. European Journal of Applied Physiology 2012 112 1123–1131. (doi:10.1007/s00421-011-2077-y).
- 126↑
Ko YH, Moon du G, Moon KH. Testosterone replacement alone for testosterone deficiency syndrome improves moderate lower urinary tract symptoms: one year follow-up. World Journal of Men's Health 2013 31 47–52. (doi:10.5534/wjmh.2013.31.1.47).
- 127↑
Rodriguez-Tolrà J, Torremadé Barreda J, del Rio L, di Gregorio S, Franco Miranda E. Effects of testosterone treatment on body composition in males with testosterone deficiency syndrome. Aging Male 2013 16 184–190. (doi:10.3109/13685538.2013.839648).
- 128↑
Pexman-Fieth C, Behre HM, Morales A, Kan-Dobrosky N, Miller MG. A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel. Aging Male 2014 17 1–11. (doi:10.3109/13685538.2013.858113).
- 129↑
Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. Randomized clinical trial of testosterone replacement therapy in hypogonadal men. International Journal of Andrology 1988 11 247–264. (doi:10.1111/j.1365-2605.1988.tb00999.x).
- 130↑
Sorva R, Kuusi T, Taskinen MR, Perheentupa J, Nikkilä EA. Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males. Atherosclerosis 1988 69 191–197. (doi:10.1016/0021-9150(88)90014-7).
- 131↑
Gregory JW, Greene SA, Thompson J, Scrimgeour CM, Rennie MJ. Effects of oral testosterone undecanoate on growth, body composition, strength and energy expenditure of adolescent boys. Clinical Endocrinology 1992 37 207–213. (doi:10.1111/j.1365-2265.1992.tb02312.x).
- 132↑
Salehian B, Wang C, Alexander G, Davidson T, McDonald V, Berman N, Dudley RE, Ziel F, Swerdloff RS. Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate – a clinical research center study. Journal of Clinical Endocrinology and Metabolism 1995 80 3567–3575.
- 133↑
Ozata M, Yildirimkaya M, Bulur M, Yilmaz K, Bolu E, Corakci A, Gundogan MA. Effects of gonadotropin and testosterone treatments on Lipoprotein(a), high density lipoprotein particles, and other lipoprotein levels in male hypogonadism. Journal of Clinical Endocrinology and Metabolism 1996 81 3372–3378.
- 134↑
Tripathy D, Shah P, Lakshmy R, Reddy KS. Effect of testosterone replacement on whole body glucose utilisation and other cardiovascular risk factors in males with idiopathic hypogonadotrophic hypogonadism. Hormone and Metabolic Research 1998 30 642–645. (doi:10.1055/s-2007-978950).
- 135↑
Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C et al.. Testosterone dose-response relationships in healthy young men. American Journal of Physiology. Endocrinology and Metabolism 2001 281 E1172–E1181.
- 136↑
Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clinical Endocrinology 2003 58 632–638. (doi:10.1046/j.1365-2265.2003.01764.x).
- 137↑
Andrade ES Jr, Clapauch R, Buksman S. Short term testosterone replacement therapy improves libido and body composition. Arquivos Brasileiros de Endocrinologia e Metabologia 2009 53 996–1004. (doi:10.1590/S0004-27302009000800014).
- 138↑
Wu XY, Mao JF, Lu SY, Zhang Q, Shi YF. Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients. Chinese Medical Journal 2009 122 2846–2850.
- 139↑
Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF, Jones BF, Barry CV, Wulczyn KE, Thomas BJ et al.. Gonadal steroids and body composition, strength, and sexual function in men. New England Journal of Medicine 2013 369 1011–1022. (doi:10.1056/NEJMoa1206168).
- 140↑
Vignozzi L, Filippi S, Comeglio P, Cellai I, Sarchielli E, Morelli A, Rastrelli G, Maneschi E, Galli A, Vannelli GB et al.. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. Molecular and Cellular Endocrinology 2014 384 143–154. (doi:10.1016/j.mce.2014.01.014).
- 141↑
Corona G, Mondaini N, Ungar A, Razzoli E, Rossi A, Fusco F. Phosphodiesterase Type 5 (PDE5) Inhibitors in erectile dysfunction: the proper drug for the proper patient. Journal of Sexual Medicine 2011 8 3418–3432. (doi:10.1111/j.1743-6109.2011.02473.x).
- 142↑
Cochrane Handbook for Systematic Reviews of Interventions. Available at: www.cochrane-handbook.org (Last accessed 22 July 2014)
- 143↑
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994 50 1088–1101. (doi:10.2307/2533446).
- 144↑
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 1997 315 629–634. (doi:10.1136/bmj.315.7109.629).
- 145↑
Cohen, J. (1977) Statistical Power Analysis for the Behavioral Sciences. Academic Press, New York
- 146↑
Maneschi E, Morelli A, Filippi S, Cellai I, Comeglio P, Mazzanti B, Mello T, Calcagno A, Sarchielli E, Vignozzi L et al.. Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. Journal of Endocrinology 2012 215 347–362. (doi:10.1530/JOE-12-0333).