Background
Methods
Data sources and searches
Study selection
CV risks following TRT
Elevation of serum T and DHT following TRT
Outcome
Data extraction and quality assessment
Statistical methods
CV events analysis
Analysis of serum T and DHT levels
Results
Study selection and characteristics for analysis of CV risks
Author/Year | Mode | Dose | Study duration | Age | Subjects in TRT group | Subjects in placebo group | Serum T at entry | Health status |
---|---|---|---|---|---|---|---|---|
Amory 2004 [32] | i.m. | 100 mg TE/week | 36 months | 71 ± 4 (SD) | 24 | 24 | 302 ± 48 (SD) ng/dL | hypogonadal |
Aversa 2010 [33] | i.m. | 1,000 mg TU/12 week | 24 months | 58 ± 10 (SD) | 40 | 10 | 259 ± 48 (SD) ng/dL | hypogonadal |
Borst 2014 [34] | i.m. | 125 mg TE/week | 12 months | 69.2 ± 8.0 (SD) | 31 | 29 | 264 ± 92 (SD) ng/dL | hypogonadal |
Caminiti 2009 [35] | i.m. | 1,000 mg TU/8 week | 4.5 months | 66 to 76 | 35 | 35 | 230 ± 180 (SD) ng/dL | hypogonadal, heart failure |
Ferrando 2002 [36] | i.m. | 100 mg TE/week | 6 months | 67 ± 3 (SD) | 7 | 5 | <480 ng/dL | eugonadal |
Hackett 2014 [37] | i.m. | 1000 mg TU/6 to 12 weeks | 7.5 months | 18 to 80 | 97 | 102 | 301 ± 11 (SD) ng/dL | hypogonadal, type 2 diabetes |
Hall 1996 [38] | i.m. | 250 mg TE/4 weeks | 9 months | 60.8 ± 9.7 (SD) | 17 | 18 | 458 ± 187 (SD) ng/dL | eugonadal, rheumatoid arthritis |
Ho 2011 [39] | i.m. | 1,000 mg TU/10 to 14 weeks | 24 months | ≥40 | 60 | 60 | <345 ng/dL | low normal T |
Hoyos 2012 [40] | i.m. | 1,000 mg TU/6 weeks | 4.5 months | 49 ± 12 (SD) | 33 | 34 | 388 ± 152 (SD) ng/dL | eugonadal, obese, sleep apnea |
Kalichenko 2010 [41] | i.m. | 1,000 mg TU/6 to 12 weeks | 7.5 months | 49 to 53 | 113 | 71 | <345 ng/dL | low normal T, metabolic syndrome |
Kenny 2004 [42] | i.m. | 200 mg TE/3 weeks | 3 months | 81 ± 5 (SD) | 6 | 5 | 410 ± 112 (SD) ng/dL | mild cognitive impairment |
Sih 1997 [43] | i.m. | 200 mg TC/2 weeks | 12 months | 65 ± 7 (SD) | 17 | 15 | 233 ± 20 (SD) ng/dL | hypogonadal |
Svartberg 2004 [44] | i.m. | 250 mg TE/4 weeks | 6 months | 64 ± 6.5 (SD) | 15 | 14 | 590 ± 164 (SD) ng/dL | eugonadal, COPD |
Svartberg 2008 [45] | i.m. | 1,000 mg TU/6 to 12 weeks | 12 months | 69 ± 5 (SD) | 19 | 19 | 239 ± 54 (SD) ng/dL | hypogonadal |
Sheffield-Moore 2011 [46] | i.m. | 100 mg TE/week | 5 months | 73 ± 8 (SD) | 8 | 8 | <500 ng/dL | eugonadal |
Tan 2013 [47] | i.m. | 1,000 mg TU/8 weeks | 12 months | 53.8 ± 8.3 (SD) | 56 | 58 | <345 ng/dL | low normal T |
*Basaria 2010 [7] | gel | 100 to 150 mg T/day | 6 months* | 74 ± 5 (SD) | 106 | 103 | 250 ± 57 (SD) ng/dL | hypogonadal, mobility limited |
Brockenbrough 2006 [48] | gel | 100 mg T/day | 6 months | 58.9 ± 14.9 (SD) | 19 | 21 | 218 ± 64 (SD) ng/dL | hypogonadal, renal disease |
Glintborg 2013 [49] | gel | 50 to 100 mg T/day | 6 months | 62 to 72 | 20 | 18 | <210 ng/dL | hypogonadal, obese |
Hildreth 2013 [50] | gel | 25 to 50 mg T/day | 12 months | 66.6 ± 5.8 (SD) | 96 | 47 | 294 ± 38 (SD) ng/dL | hypogonadal |
Jones 2011 [51] | gel | 60 mg T/day | 12 months | 37 to 77 | 108 | 112 | 265 ± 75 (SD) ng/dL | hypogonadal, metabolic syndrome |
Kaufman 2011 [52] | gel | 20 to 80 mg T/day | 6 months | 53.6 ± 9.5 (SD) | 234 | 40 | mean =294 ng/dL | hypogonadal |
Kenny 2010 [53] | gel | 50 mg T/day | 12 to 24 months | 79.9 ± 7.3 (SD) | 69 | 62 | 380 ± (SD) ng/dL | eugonadal, osteoporosis |
Marin 1993 [54] | gel | 125 mg T/day | 9 months | 56.7 ± 2.2 (SD) | 11 | 10 | 434 ± 23 (SD) ng/dL | eugonadal, obese |
Spitzer 2012 [55] | gel | 100 to 300 mg T/day | 3.5 months | 55.1 ± 8.3 (SD) | 70 | 70 | 248 ± 62 (SD) ng/dL | hypogonadal, erectile dysfunction |
Srinivas-Shankar 2010 [56] | gel | 50 mg T/day | 6 months | 73.7 ± 5.7 (SD) | 138 | 136 | 313 ± 89 (SD) ng/dL | low normal T, frail |
English 2000 [17] | patch | 5 mg T/day | 3 months | 69 ± 2 (SD) | 25 | 25 | 390 ± 22 (SD) ng/dL | eugonadal, stable angina |
Malkin 2006 [57] | patch | 5 mg T/day | 12 months | 63.1 ± 10.7 (SD) | 37 | 39 | 400 ± 152 (SD) ng/dL | eugonadal, heart failure |
Merza 2005 [58] | patch | 5 mg T/day | 6 months | 63 ± 9 (SD) | 20 | 19 | 242 ± 95 (SD) ng/dL | hypogonadal |
Nair 2006 [59] | patch | 5 mg T/day | 24 months | 61 to 72 | 27 | 31 | bioavailable T <103 ng/dL | hypogonadal |
Snyder 2001 [60] | patch | 6 mg T/day | 36 months | 71.3 ± 5.8 (SD) | 54 | 54 | <475 ng/dL | eugonadal |
Chapman 2009 [61] | oral | 160 mg TU/day | 12 months | 78 ± 4 (SD) | 11 | 12 | 541 ± 35 (SD) ng/dL | eugonadal, undernourished |
Copenhagen study 1986 [62]a
| oral | 600 mg micronized T/day | 8 to 62 months | 24 to 79 | 134 | 87 | not measured | alcoholic cirrhosis |
Emmelot-Vonk 2008 [63] | oral | 80 mg TU/day | 6 months | 67.1 ± 5.0 (SD) | 120 | 117 | 316 ± 54 (SD) ng/dL | low normal T |
Legros 2009 [64] | oral | 80 to 240 mg TU/day | 12 months | 58.6 ± 5.7 (SD) | 237 | 79 | free T <7.5 ng/dL | hypogonadal |
Risk of CV events based on route of TRT
Route of TRT and elevation of serum T and DHT Levels
Author/Year | Study type | Mode | Dose | Duration | Age | Subjects in TRT group | Serum T at entry | Health status |
---|---|---|---|---|---|---|---|---|
Amory 2004 [32] | RCT | i.m. | 100 mg TE/week | 36 months | 71 ± 4 (SD) | 24 | 302 ± 48 (SD) ng/dL | hypogonadal |
Arver 1997 [65] | open-label | i.m. | 266 mg TE/26 days | 3 weeks | 58 ± 10 (SD) | 27 | 121 ± 100 (SD) ng/dL | hypogonadal |
Bhasin 2012 [66] | RCT | i.m. | 125±mg TE/week | 5 months | 40 ± 7 (SD) | 12 | 519 ng/dL (mean) | eugonadal |
Borst 2014 [34] | RCT | i.m. | 125 mg TE/week | 12 months | 69.2 ± 8.0 (SD) | 31 | 264 ± 92 (SD) ng/dL | hypogonadal |
Lakshman 2010 [67] | RCT | i.m. | 125 mg TE/week | 5 months | 65.6 ± 4.3 (SD) | 11 | 581 ± 168 (SD) ng/dL | eugonadal |
Raynaud 2008 [68] | open-label | i.m. | 250 mg TE/3 weeks | 12 months | 41.8 ± 12.4 (SD) | 32 | 43 ng/dL (mean) | hypogonadal |
Shubert 2003 [69] | open-label | i.m. | 250 mg TE/3 weeks | 12 months | 31.9 ± 2.5 (SD) | 14 | 63.6 ng/dL ±14 (SD) | hypogonadal |
Wang 2010 [70] | open-label | i.m. | 750 mg TU/4 to 10 weeks | 21 months | >18 | 117 | 320 ng/dL ±111 (SD) | low normal T |
Brockenbrough 2006 [48] | RCT | gel | 10 mg T/day | 6 months | 58.9 ± 14.9 (SD) | 19 | 218 ± 64 (SD) ng/dL | hypogonadal, renal disease |
Cherrier 2003 [71] | RCT | gel | 50-100 mg T/day | 6 months | 34 to 70 | 12 | 320 ± 90 (SD) ng/dL | low normal T |
Chiang 2007 [72] | RCT | gel | 50 mg T/day | 3 months | 20 to 75 | 17 | 213 ± 158 (SD) ng/dL | hypogonadal |
Dean 2004 [73] | open-label | gel | 50 mg T/day | 9 months | 58.5 (mean) | 257 | 247 ng/dL (mean) | hypogonadal |
Di Luigi 2012 [74] | open-label | gel | 50 mg T/day | 1.25 month | 31.3 ± 7.5 (SD) | 10 | 72 ng/dL (mean) | hypogonadal |
Juang 2014 [75] | RCT | gel | 100 mg T/day | 3.5 months | 24 to 51 | 14 | 302 ± 37 (SD) ng/dL | hypogonadal, osteoporosis |
Kenny 2010 [53] | RCT | gel | 50 mg T/day | 12 months | 79.9 ± 7.3 (SD) | 69 | 380 ± 179 (SD) ng/dL | eugonadal, osteoporosis |
Marin 1993 [54] | RCT | gel | 125 mg T/day | 9 months | 56.7 ± 2.2 (SD) | 10 | 455 ± 23 (SD) ng/dL | eugonadal, obese |
Mazer 2005 [76] | RCT | gel | 59 mg/day | 2 weeks | 52.4 ± 12.2 (SD) | 28 | 226 ± 110 (SD) ng/dL | hypogonadal |
Page 2011 [77] | RCT | gel | 75 mg T/day | 6 months | >50 | 27 | 204 ng/dL (mean) | hypogonadal, BPH |
Swerdloff 2000 [78] | open-label | gel | 100 mg T/day | 3 months | 51.3 (mean) | 76 | 280 ng/dL (mean) | hypogonadal |
Wang 2000 [79] | no placebo group | gel | 100 mg T/day | 2 weeks | 26 to 59 | 10 | 179 ± 41 (SD) ng/dL | hypogonadal |
Wang 2011 [80] | open-label | gel | 60 mg T/day | 4 months | 51.5 ± 12.7 (SD) | 135 | 215 ± 84 (SD) ng/dL | hypogonadal |
Ahmed 1988 [81] | no placebo group | patch | 15 mg T/day | 6 to 8 weeks | 34 to 54 | 5 | 45 ± 12 (SD) ng/dL | hypogonadal |
Bals-Pratch 1988 [82] | not stated | patch | 10 to 15 mg T/day | 14 months | 31 to 37 | 7 | 189 ng/dL (mean) | hypogonadal |
Behre 1999 [83] | open-label | patch | 2.4 to 3.6 mg T/day | 7 years | 35.9 ± 9.8 (SD) | 11 | 147 ± 37 (SD) ng/dL | hypogonadal |
Cunningham 1989 [84] | placebo-controlled | patch | 15 mg T/day | 8 weeks | 33 to 66 | 12 | 43 ± 11 (SD) ng/dL | hypogonadal |
Mazer 2005 [76] | open-label | patch | 5 mg T/day | 2 weeks | 28 to 71 | 28 | 215 ± 110 (SD) ng/dL | hypogonadal |
Meikle 1992 [85] | not stated | patch | 12.6 mg T/day | single dose | 24 to 66 | 6 | 161 ± 27 (SD) ng/dL | hypogonadal |
Raynaud 2008 [68] | open-label | patch | 2.5 mg T/day | 12 months | 40.7 ± 10.5 (SD) | 131 | 43 ng/dL (mean) | hypogonadal |
Franchimont 1978 [86] | oral | 120 to 240 mg TU/day | 9 weeks | 16 to 51 | 10 | 120 ng/dL (mean) | hypogonadal | |
Roth 2011 [87] | open-label | oral | 400 mg TU/day | 1 day | 18 to52 | 11 | 405 ± 14 (SD) ng/dL | eugonadal |
Schubert 2003 [69] | open-label | oral | 160 mg TU/day | 12 months | 34.5 ± 3.9 (SD) | 13 | 63.6 ng/dL ±14 (SD) | hypogonadal |
Van Coevorden 1986 [88] | RCT | oral | 240 mg TU/day | 12 weeks | 40 ± 11 (SD) | 19 | 161 ± 86 (SD) ng/dL | hypogonadal, renal insufficiency |
Testosterone | DHT | ||||||
---|---|---|---|---|---|---|---|
Route of administration | Number of studies | Pre-treatment T (nmol/L) (95% CI) | Post-treatment T (nmol/L) (95% CI) | Pre-Post treatment fold increase in T (95% CI) | Pre-treatment DHT (nmol/L) (95% CI) | Post-treatment DHT (nmol/L) (95% CI) | Pre-Post treatment fold increase in DHT (95% CI) |
Intramuscular | 8 | 9.27 (5.68 to 12.85) | 23.11 (15.38 to 34.72) | 2.91 (2.19 to 3.86) | 1.02 (0.69 to 1.34) | 1.62 (1.2 to 2.19) | 2.20 (1.74 to 2.77) |
Transdermal (patch and gel) | 20 | 7.28 (6.09 to 8.42) | 16.69 (12.62 to 21.98) | 2.53 (1.83 to 3.50) | 0.99 (0.78 to 1.20) | 3.43 (2.37 to 4.98) | 5.46 (4.51 to 6.60) |
Gel | 13 | 8.90 (7.67 to 10.13) | 18.3 (15.18 to 23.12) | 1.98 (1.70 to 2.30) | 1.19 (0.93 to 1.46) | 3.81 (2.57 to 5.63) | 5.12 (4.07 to 6.45) |
Patch | 7 | 4.20 (2.78 to 5.23) | 9.73 (4.01 to 23.62) | 4.43 (2.99 to 6.54) | 0.62 (0.36 to 0.88) | 2.16 (0.68 to 6.87) | 6.61 (3.08 to 14.16) |
Orala
| 4 | 6.66 | 21.88 | 2.80 | 0.90 | 3.92 | 4.46 |
(14.05, 2.9, 5.6, 4.1) | (59.2, 5.70, 7.6, 14.96) | (4.20, 2.20, 1.4, 3.6) | (1.1, 1.8, 0.30, 0.41) | (9.89, 3.30, 1.13, 1.35) | 9.0, 1.8, 3.8, 3.3 |