Table 1: Baseline characteristics of included studies
Study | Study design | Total no of patients | Hypogonadism cut off point | No of patients | Age (Mean ±SD) | Waist circumference (cm) (Mean ±SD) | BMI (Kg/m2) (Mean ±SD) |
TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo |
Dhindsa (2015)[13] | RCT | 34 | FT<225 pmmol/L | 20 | 14 | 54.6± 7.9 | 54.6± 7.9 | 128 ±20 | 124 ± 30 | 39.0 ± 7.6 | 39.4 ± 7.9 |
Gianatti (2014)[8] | RCT | 67 | TT<12 nmmol/L | 37 | 30 | 62± 2.5 | 62± 2.5 | 110±4.2 | 115±2.75 | | |
Hackett (2014)[14] | RCT | 186 | TT<12 nmmol/L | 91 | 95 | 61.2 ± 10.5 | 62.0 ± 9.3 | 115.1 ± 13.1 | 112.6 ± 13.3 | 33.0 ± 6.1 | 32.4 ± 5.5 |
Jones (2011)[15] | RCT | 137 | TT<11 nmmol/L | 68 | 69 | 59.9± 9.1 | 59.9 ± 9.4 | 112.7± 13.35 | 111.7± 15.23 | 32.76± 6.12 | 31.56 ± 5.87 |
Gopal (2010)[16] | RCT crossover | 22 | FT<225 pmmol/L | 22 | 22 | 44.23 ±3.29 | 44.23 ±3.29 | 93.25 ± 7.03 | 84.10 ± 13.86 | 25.44 ± 3.57 | 22.10 ± 4.93 |
Heufelder (2009)[17] | RCT | 32 | TT<11 nmmol/L | 16 | 16 | 57.3 ±1.4 | 55.9 ±1.5 | 107.9 ± 1.3 | 105.7± 1.4 | 32.1 ± 0.5 | 32.5 ± 0.6 |
Kapoor (2006)[18] | RCT crossover | 27 | TT<12 nmmol/L | 24 | 24 | 64 ±1.34 | 64 ±1.34 | 115.1± 2.4 | 115.1± 2.4 | 33 ±0.86 | 33 ±0.96 |
Boyanov (2003)[19] | RCT | 48 | TT<15 nmmol/ | 24 | 24 | 57.5 ± 4.8 | 57.5 ± 4.8 | N/A | N/A | 31.08 ± 4.79 | 31.01 ± 4.90 |
Hackett (2018)[20] | RCT | 537 | TT<12 nmmol/L | 175 | 362 | 58.3± 11 | 65.5 ± 11.8 | N/A | N/A | 32.6 ± 6.4 | 31.7± 5.9 |
Yassin (2019)[12] | Observational study | 316 | TT< 12.1nmol/L | 229 | 87 | 58.2 ± 9.6 | 66.4 ± 7.2 | 104.2 ± 7 | 101.1 ± 9.9 | 30.7 ± 4.1 | 29.8 ± 3 |
Khirpun (2018)[21] | RCT | 80 | serum levels of total testosterone two times below 12.1 nmol/L or serum levels of free testosterone two times below 243 pmol/L in combination of at least two symptoms or complaints of sexual or psychological nature | 40 | 40 | 53.3 ± 5.4 | 54.1 ± 5.6 | 114.3 ± 9.5 | 114.7 ± 9.8 | 34.0 ± 2.6 | 33.6 ± 2.9 |
Groti (2020)[5] | RCT | 55 | (total testosterone [TT] below 11 nmol/L and free testosterone below 220 pmol/L) on at least two separate morning measurements after an overnight fast in addition to exhibiting at least two symptoms of sexual dysfunction (less frequent morning e | 28 | 27 | 58.21 ± 7.94 | 62.19 ± 5.90 | 116.48 ± 5.07 | 115 ± 1.47 | 34.03 ± 4.37 | 32.63 ± 3.67 |
Groti (2018)[22] | RCT | 55 | total testosterone (TT) level <11 nmol/l and/or free testosterone (FT) level <220 pmol/l | 28 | 27 | N/A | N/A | 116.48 ± 5.07 | 116.64 ± 4.96 | 34.03 ± 4.37 | 32.63 ± 3.67 |
Wittert (2021) [23] | RCT | 1007 | 13·0 nmol/L | 504 | 503 | 59·8 ± 6·3 | 59·6 ± 6·4 | 118·4 ± 12·6 | 117·8 ± 11·6 | 34·8 (5·1) | 34·6 (5·1) |
Haider (2020) [24] | Prospective observational | 356 | total testosterone levels ≤12.1 nmol/L (350 ng/dL) and symptoms of hypogonadism | 178 | 178 | 61.5 ± 5.4 | 63.7 ± 4.9 | 116.8 ± 14.3 | 116.9 ± 13.6 | 36.5 ± 4.5 | 33.4 ± 5.3 |
SD: Standard deviation, Ft: free testosterone, TT: total testosterone
Table 2: Baseline glucometabolic, lipid and blood pressure parameters
Study | Fasting plasma glucose (mmol/L) (Mean ±SD) | Fasting serum insulin (Mean ±SD) | HbA1c % | Free testosterone (Mean ±SD) | Total testosterone (Mean ±SD) | HOMA-IR (Mean ±SD) | Mean total cholesterol (Mean ±SD) | Systolic blood pressure (Mean ±SD) | Diastolic blood pressure (Mean ±SD) |
| TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo | TRT | Placebo |
Dhindsa (2015)[13] | 6.99 ± 0.44 | 6.60 ± 0.55 | 13.6 ± 3 | 11.8 ± 2.2 | 6.8 ± 0.9 | 7 ±1.4 | 156.5 ± 45.11 | 145.74 ± 41.6 | 9 ± 2.9 | 8.3 ± 2.8 | 9 ± 2.9 | 8.3 ± 2.8 | 4.06 ± 0.98 | 4.03 ±0.95 | N/A | N/A | N/A | N/A |
Gianatti (2014)[8] | 9.57 ± 3.78 | 9.11 ± 3.65 | N/A | N/A | 7.7 ± 1.3 | 7.5 ± 1.2 | 187.7 ± 57.0 | 181.2 ± 63.6 | 9.2 ± 3.1 | 8.9 ± 3.8 | 4.1 ± 2.0 | 3.7 ± 2.6 | 4.15± 0.90 | 4.08± 0.9 | 140.2 ± 15.9 | 137.1 ± 13.0 | 79.4 ± 9.4 | 77.5 ± 8.9 |
Hackett (2014)[14] | 9.05 ± 3.18 | 8.49 ± 2.84 | 20.88 ± 22.83 | 18.17 ± 15.7 | N/A | N/A | 198 ± 49.3 | 202.4 ± 62.1 | 9.2± 2.6 | 9.5± 3.3 | 5.9± 3.8 | 4.9± 3.3 | 4.51± 1.17 | 4.55± 1.01 | 138.6± 17.30 | 136.7± 17.12 | 82.5± 10.23 | 81.6± 9.50 |
Jones (2011)[15] | 7.9 ± 4.3 | 9.2 ± 3.4 | 12.80 ± 8.95 | 17.86 ± 24.72 | 6.43 ± 2.20 | 7.69 ± 2.77 | 177.57 ± 60.19 | 177.57 ± 60.19 | 10.1 ± 3.7 | 10.1 ± 3.7 | 5.50 ± 6.82 | 6.45 ± 8.75 | 4.7 ± 0.9 | 4.0 ± 1.0 | 115.83 ± 5.15 | 118.40 ± 9.97 | 82.00 ± 6.93 | 79.00 ± 3.16 |
Gopal (2010)[16] | 7.9 ± 0.2 | 8.3 ± 0.2 | 19.03 ± 0.63 | 16.8 ± 0.87 | 7.5 ± 0.1 | 7.5 ± 0.1 | 200 ± 0.00 | 200 ± 0.00 | 10.5 ± 0.2 | 10.4 ±0.2 | 5.6 ± 0.3 | 6.1 ± 0.4 | N/A | N/A | 104.5± 2.6 | 143.5± 2.1 | 85.6± 0.9 | 85.0± 1.0 |
Heufelder (2009)[17] | 7.83 ± 0.49 | 7.6 ± 0.43 | 13.68 ± 1.95 | 12.37 ± 1.87 | 7.28 ±0.19 | 7.28 ±0.19 | N/A | N/A | 8.63 ±0.51 | 8.63 ±0.51 | N/A | N/A | 5.11 ±0.17 | 4.95± 0.15 | 127.6± 2.8 | 131± 3.1 | 74± 1.4 | 74± 1.4 |
Kapoor (2006)[18] | 8.0 ± 2.6 | 8.4 ± 2.8 | N/A | N/A | 10.4 ± 1.6 | 10.3 ± 1.6 | N/A | N/A | 9.56 ± 2.33 | 10.76 ± 3.0 | N/A | N/A | 5.50 ± 1.41 | 5.59 ± 1.49 | 122 ± 8 | 120 ± 8 | 80 ± 4 | 76 ± 6 |
Boyanov (2003)[19] | N/A | N/A | N/A | N/A | 7.6 ± 1.3 | 7.5 ± 1.5 | 210 ± 124.5 | 175 ± 67.9 | 9.7 ± 4.4 | 8.9 ± 3.2 | N/A | N/A | 4.5 ± 1.1 | 4.1 ± 1.0 | 141.8± 16.1 | 139.4± 16.8 | 81.4 ± 10.4 | 78.2 ± 10.4 |
Hackett (2018)[20] | 5.3 ± 0.8 | 4.9 ± 1.3 | N/A | N/A | 5.9 ± 0.2 | 5.9 ± 0.2 | N/A | N/A | 8.2 ± 2.1 | 9.6 ± 2.4 | N/A | N/A | 6.9 ± 1.2 | 6.4 ± 1.4 | 136.9 ± 13.5 | 129.8 ± 12.7 | 81.2 ± 8.9 | 84.7 ± 6.7 |
Yassin (2019)[12] | 8.1 ± 3.7 | 8.7 ± 5.0 | N/A | N/A | 7.8 ± 2.4 | 7.9 ± 2.4 | 208 ± 142 | 223 ± 140 | 9.6 ± 2.7 | 9.9 ± 2.6 | N/A | N/A | 6.1 ± 1.2 | 5.9 ± 1.5 | N/A | N/A | N/A | N/A |
Khirpun (2018)[21] | 10.06 ± 1.44 | 9.77 ± 1.40 | N/A | N/A | 8.12 ± 1.04 | 7.89 ± 0.77 | 208 ± 142 | 223 ± 140 | 7.24 ± 1.97 | 7.96 ± 1.34 | 11.45 ± 7.34 | 10.82 ± 6.52 | 5.31 ± 0.91 | 5.11 ± 0.85 | 134.64 ± 10.71 | 138.15 ± 13.24 | 77.50 ± 5.85 | 78.89 ± 5.25 |
Groti (2020)[5] | 10.06 ± 1.44 | 9.60 ± 1.44 | 26.03 ± 15.86 | 24.89 ± 13.90 | 8.12 ± 1.04 | 7.89 ± 0.77 | N/A | N/A | 7.24 ± 1.97 | 7.96 ± 1.34 | 11.45 ± 7.34 | 10.70 ± 6.52 | 5.31 ± 0.91 | 5.31 ± 0.97 | 134.64 ± 10.71 | 138.15 ± 13.24 | 77.50 ± 5.85 | 78.89 ± 5.25 |
Groti (2018)[22] | 10.06 ± 1.44 | 9.60 ± 1.44 | 26.03 ± 15.86 | 24.89 ± 13.90 | 8.12 ± 1.04 | 7.89 ± 0.77 | N/A | N/A | 7.24 ± 1.97 | 7.96 ± 1.34 | 11.45 ± 7.34 | 10.70 ± 6.52 | 5.31 ± 0.91 | 5.31 ± 0.97 | 134.64 ± 10.71 | 138.15 ± 13.24 | 77.50 ± 5.85 | 78.89 ± 5.25 |
Wittert (2021) [23] | 6·1 ± 0·9 | 6·1 ± 0·9 | N/A | N/A | 5·7 ± 0·5 | 5·7 ± 0·5 | N/A | N/A | 13·4 ± 4·1 | 13·9 ± 4·6 | N/A | N/A | N/A | N/A | 138.52± 14.2 | 139.88± 14 | 85.45± 8.5 | 85.13± 8.3 |
Haider (2020) [24] | 7.8 ± 1.2 | 6.3 ± 0.7 | 28.6 ± 4.0 | 24.9 ± 2.9 | Forest plot | Forest plot | N/A | N/A | 9.3 ± 1.7 | 9.8 ± 1.1 | 9.8 ± 2.0 | 7.1 ± 1.3 | 8.3 ± 1.1 | 7.1 ± 1.2 | 163.0 ± 13.3 | 145.6 ± 14.6 | 97.6 ± 10.8 | 84.8 ± 10.3 |
SD: Standard deviation, HOMA-IR: Homeostasis model of insulin resistance, HbA1c: glycated hemoglobin
Table 3: Secondary outcomes
Outcome | Testosterone | placebo | Effect size [CI] | Overall P value | heterogeneity |
Total cholesterol | -0.71 [-1.22, -0.21] | 0.10 [-016, 0.35] | -0.32 [-0.64, 0.00] | 0.05 | 87.2 |
Triglyceride | -0.47 [-0.75, - 0.20] | 0.03 [-021, 0.27] | -0.23 [-0.47, 0.00] | 0.05 | 86.6 |
LDL cholesterol | -0.20 [-1.12, 0.73] | 0.17 [-0.13, 0.46] | -0.02 [-0.52, 0.48] | 0.94 | 0 |
HDL cholesterol | 0.10 [0.01, 0.20] | 0.03 [-0.07, 0.13] | 0.07 [0.00, 0.13] | 0.04 | 8.7 |
Body fat | -0.98 [-1.59, -0.38] | -0.54 [-1.12, 0.03] | -0.75 [-1.17, -0.34] | 0.0004 | 6.4 |
Waist circumference | -3.98 [-6.48, -1.48] | 0.73 [-1.44, 2.89] | -1.68 [3.43, 0.07] | 0.06 | 87.1 |
BMI | -1.12 [-2.98, 0.74] | 0.05 [-0.51, 0.61] | -0.56 [-1.48, 0.36] | 0.23 | 27.5 |
SBP | -0.90 [-12.07, 10.26] | -0.19 [-3.19, 2.81] | -0.51 [-6.24, 5.11] | 0.85 | 0 |
DBP | -3.09 [-5.52, -0.65] | -0.23 [-1.98, 1.52] | -1.68 [-3.16, -0.21] | 0.03 | 71.3 |
IIEF | 6.98 [3.62, 10.33] | -3.94 [-10.97, 3.10] | 1.66 [-6.75, 10.06] | 0.70 | 86.7 |
AMS | -16.80 [-26.96, -6.64] | 4.90 [-9.05, 18.85] | -5.94 [-21.87, 9.98] | 0.46 | 83.5 |
Mortality | - | | 0.24 [0.15, 0.37] | <0.00001 | 0 |
CI: Confidence interval, LDL: low density lipoprotein, HDL: High density lipoprotein, BMI: Body mass index; SBP: Systolic blood pressure, DBP: Diastolic blood pressure, IIEF: international index of erectile function, AMS: Aging male score.