Table 1. Observational studies (only prospective studies): the effects of total-, free-, and bioavailable-testosterone on CVD events are presented as beneficial (friendly)*, detrimental (foe)† or no effects at all (bystander)‡ in terms of their magnitude of association and statistical significance.
| Study author and year | Study design | Number of participants for independent studies | Follow-up (years) | Exposure (high levels vs. low levels or continuous increment of 1 S.D.) | Cardiovascular events (n) | Results: only fully-adjusted multivariable models | SS P<0.05 or NS |
|---|---|---|---|---|---|---|---|
| Beneficial (friendly) effects* | OR’s, RR’s or HR’s that are lower or equal to 0.90 | ||||||
| Yeap et al., 2009 (17)a | Population prospective study | 3,443 | Median follow-up 3.5 | Total testosterone, nmol/liter [high vs. low <11.7 (ref.)] | Incident stroke or TIA (n=119) | HR =0.50 | SS (P=0.001) |
| Free testosterone, pmol/liter [high vs. low <222 (ref.)] | Incident stroke or TIA (n=119) | HR =0.59 | SS (P=0.008) | ||||
| Ohlsson et al., 2011 (18) | Prospective population-based | 2,416 | Median follow-up 5 | Total testosterone, ng/dL [(high vs. low quartile, ≥550 vs. ≤340 (ref.)) | Major CV events (n=485) | HR =0.71; 95% CI, 0.54–0.93 | SS (P for trend=0.009) |
| Free testosterone, pg/mL [high vs. low quartile, ≥98.2 vs. ≤62.2 (ref.)] | Major CV events (n=485) | HR =0.84; 95% CI, 0.64–1.10 | NS | ||||
| Shores et al., 2014 (19)b | Longitudinal cohort study | 1,032 | Median follow-up 9 | Total testosterone, ng/dL (≥278 vs. <278) | Incident CVD (MI, stroke, CVD) (n=436) | HR =0.90 | NS |
| Yeap et al., 2014 (20) | Prospective community-based | 3,690 | Mean follow-up 6.6 | Free testosterone, pmol/L; Q4 (216.3–699.0) vs. Q1 (3.54–150.3) | Incident MI (n=344) | HR =0.85; 95% CI, 0.61–1.17 | NS |
| Total testosterone, nmol/L; Q4 (15.79–46.5) vs. Q1 (0.25–9.82) | Incident of stroke (n=300) | HR =0.56; 95% CI, 0.39-0.81 | SS | ||||
| Free testosterone, pmol/L; Q4 (216.3–699.0) vs. Q1 (3.5–150.4) | Incident of stroke (n=300) | HR =0.57; 95% CI, 0.39–0.81 | SS | ||||
| Hak et al., 2002 (21) | Population-based prospective study | 504 | 6.5 | Total testosterone, nmol/L; (T3 >12.6–≤36.8 vs. T1 ≥0–≤9.8) | Aortic atherosclerosis (n=329) | RR =0.40; 95% CI, 0.1–1.0 | SS (P for trend=0.04) |
| Bioavailable testosterone, nmol/L; (T3 >7.5–≤28.7 vs. T1 ≥7.5–≤28.7) | Aortic atherosclerosis (n=329) | RR =0.20; 95% CI, 0.0–0.6 | SS (P for trend=0.004) | ||||
| Khaw et al., 2007 (22)C | Nested case-control study | 1,858 | Mean follow-up 7 | Total testosterone, nmol/L (Q4 >19.6 vs. Q1 <12.5) | CVD mortality (n=369) | OR =0.53; 95% CI, 0.32–0.86 | SS (P for trend <0.01) |
| Detrimental (foe) effects† | OR’s, RR’s or HR’s that are higher or equal to 1.10 | ||||||
| Vikan et al., 2009 (23) | Population-based prospective study | 1,568 | 9.1 | Free testosterone (continuous increment 1 S.D.) | IHD mortality (n=80) | HR =1.16; 95% CI, 0.90–1.49 | NS |
| 1,318 | 9.1 | Total testosterone [higher vs. lower quartile: >16.2 vs. <9.7 (ref.)] | First-ever MI (n=144) | HR =1.14; 95% CI, 0.68–1.89 | NS | ||
| Soisson et al., 2013 (24) | Prospective cohort study | 495 | 4 | Total testosterone, ng/mL; [Q5 ≥6.89 vs. Q2 3.94–4.88 (ref.)] | IAD (n=146) | HR =3.61; 95% CI, 1.55–8.45 | SS |
| Bioavailable testosterone, ng/mL; [Q5 ≥4.02 vs. Q2 2.35–2.87 (ref.)] | IAD (n=146) | HR =1.99; 95% CI, 0.90–4.35 | NS | ||||
| Shores et al., 2014 (25) | Prospective cohort study | 1,032 | Median follow-up 10 | Total testosterone, ng/dL; [Q5 >800 vs. Q3 400–600 (ref.)] | Incident ischemic stroke (n=114) | HR =1.69; 95% CI, 0.51–5.60 | NS |
| Shores et al., 2014 (19)b | Longitudinal cohort study | 1,032 | Median follow-up 9 | Free testosterone, ng/dL; (≥4.1 vs. <4.1) | Incident CVD (MI, stroke, CVD) (n=436) | HR =1.15 | NS |
| No effects at all (bystander)‡ | Neither beneficial nor detrimental | ||||||
| Smith et al., 2005 (26) | Prospective study | 2,212 | 16.5 | Total testosterone (continuous increment 1 S.D.) | Fatal IHD (n=192) | HR =0.94; 95% CI, 0.80–1.11; €P=0.61 | NS |
| Non-fatal IHD (n=320) | OR =0.97; 95% CI, 0.84–1.12 | NS | |||||
| Vikan et al., 2009 (23) | Population-based prospective study | 1,568 | 9.1 | Total testosterone (continuous increment 1 S.D.) | CVD mortality (n=133) | HR =0.96; 95% CI, 0.80-1.15; €P =0.68 | NS |
| Free testosterone (continuous increment 1 S.D.) | CVD mortality (n=133) | HR =0.99; 95% CI, 0.80–1.23 | NS | ||||
| Total testosterone (continuous increment 1 S.D.) | IHD mortality (n=80) | HR =1.03; 95% CI, 0.82–1.29 | NS | ||||
| 1,318 | 9.1 | Total testosterone (continuous increment 1 S.D.) | First-ever MI (n=144) | HR =1.03; 95% CI, 0.86–1.23 | NS | ||
| Free testosterone (continuous increment 1 S.D.) | First-ever MI (n=143) | HR =1.01; 95% CI, 0.83–1.24 | NS | ||||
| Free testosterone [higher vs. lower quartile: >241 vs. <159 (ref.)] | First-ever MI (n=143) | HR =0.96; 95% CI, 0.58–1.59 | NS | ||||
| Haring et al., 2013 (27)d | Prospective community-based | 254 | 5 | Total testosterone, ng/mL baseline | Incident clinical CVD (n=56) | HR =0.98; 95% CI, 0.77–1.25 | NS |
| Total testosterone, ng/mL; meand-average | Incident clinical CVD (n=56) | HR =1.04; 95% CI, 0.81–1.33 | NS | ||||
| 10 | Total testosterone, ng/mL baseline | Incident clinical CVD (n=92) | HR =1.04; 95% CI, 0.86–1.26 | NS | |||
| Total testosterone, ng/mL; meand | Incident clinical CVD (n=92) | HR =1.05; 95% CI, 0.87–1.27 | NS | ||||
| Yeap et al., 2014 (20) | Prospective community-based | 3,690 | Mean follow-up 6.6 | Total testosterone, nmol/L; Q4 (15.79–46.50) vs. Q1 (0.25–9.82) | Incident MI (n=344) | HR =0.92; 95% CI, 0.66–1.28 | NS |
*, beneficial (friendly) effects is the magnitude of association such as odd ratios (OR’s), rate ratios (RR’s), or hazard ratios (HR’s) whether they are below or equal to 0.90; †, detrimental (foe) effects if the OR’s, RR’s or HR’s are greater or equal to 1.10; ‡, no effects at all (bystander) if it is neither friendly nor foe; €, P trend for comparing highest quintiles of testosterone versus lowest quintile (HR for fatal IHD =0.93 and HR for non-fatal IHD =1.02, no 95% CI’s were provided); a, Yeap—we used the reciprocal of low testosterone vs. high testosterone to show the risk of stroke by comparing high vs. low testosterone levels; b, Shoes—we used the reciprocal of low testosterone vs. high testosterone to show the Incident CVD (MI, stroke, CVD) by comparing high vs. low testosterone levels; c, this nested case-control study included an average follow-up time of 7 years to assess the risk of CVD mortality. Therefore, we included in this table of prospective studies; d, mean: average sex steroid concentration calculated in each individual using measures from at least two and up to four examinations; SS, statistically significant; NS, not statistically significant; TIA, transient ischemic attack; IAD, ischemic arterial disease; IHD, ischemic heart disease; CVD, cardiovascular disease.