Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis

Stephen E Borst, Jonathan J Shuster, Baiming Zou, Fan Ye, Huanguang Jia, Anita Wokhlu, Joshua F Yarrow, Stephen E Borst, Jonathan J Shuster, Baiming Zou, Fan Ye, Huanguang Jia, Anita Wokhlu, Joshua F Yarrow

Abstract

Background: Potential cardiovascular (CV) risks of testosterone replacement therapy (TRT) are currently a topic of intense interest. However, no studies have addressed CV risk as a function of the route of administration of TRT.

Methods: Two meta-analyses were conducted, one of CV adverse events (AEs) in 35 randomized controlled trials (RCTs) of TRT lasting 12 weeks or more, and one of 32 studies reporting the effect of TRT on serum testosterone and dihydrotestosterone (DHT).

Results: CV risks of TRT: Of 2,313 studies identified, 35 were eligible and included 3,703 mostly older men who experienced 218 CV-related AEs. No significant risk for CV AEs was present when all TRT administration routes were grouped (relative risk (RR) = 1.28, 95% confidence interval (CI): 0.76 to 2.13, P = 0.34). When analyzed separately, oral TRT produced significant CV risk (RR = 2.20, 95% CI: 1.45 to 3.55, P = 0.015), while neither intramuscular (RR = 0.66, 95% CI: 0.28 to 1.56, P = 0.32) nor transdermal (gel or patch) TRT (RR = 1.27, 95% CI: 0.62 to 2.62, P = 0.48) significantly altered CV risk. Serum testosterone/DHT following TRT: Of 419 studies identified, 32 were eligible which included 1,152 men receiving TRT. No significant difference in the elevation of serum testosterone was present between intramuscular or transdermal TRT. However, transdermal TRT elevated serum DHT (5.46-fold, 95% CI: 4.51 to 6.60) to a greater magnitude than intramuscular TRT (2.20-fold, 95% CI: 1.74 to 2.77).

Conclusions: Oral TRT produces significant CV risk. While no significant effects on CV risk were observed with either injected or transdermal TRT, the point estimates suggest that further research is needed to establish whether administration by these routes is protective or detrimental, respectively. Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route, as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies.

Figures

Figure 1
Figure 1
Selection process for placebo-controlled randomized clinical trials (RCTs) of testosterone replacement therapy (TRT) on CV events.
Figure 2
Figure 2
Forest plot of all placebo-controlled randomized clinical trials (RCTs) reporting the pooled effect of testosterone replacement therapy (TRT) and the individual effects by TRT administration route on CV events.
Figure 3
Figure 3
Selection process for clinical trials reporting both serum testosterone (T) and dihydrotestosterone (DHT) concentrations before and after testosterone replacement therapy (TRT).
Figure 4
Figure 4
Comparison of DHT levels after testosterone treatment with DHT levels that are associated with cardiovascular disease risk. Left panel. Testosterone-induced elevation of DHT in the eight RCTs of testosterone injection, twenty RCTs of transdermal administration and four RCTs of oral testosterone administration shown in Table 2. Transdermal administration causes a greater elevation of serum DHT. Center panel. Data from panel 1 is overlayed on observational data from Shores et al. showing the relationship between serum DHT and 10 year risk of incident ischemic stroke in older men. The solid line represents the estimated hazard ratio (HR) and the shaded area depicts the 95% confidence interval. All models are adjusted for age (reprinted with permission from Shores et al. Clin Endocrinol (Oxf) 2014. doi: 10.1111/cen.12452 [22]. Right panel. Data from panel 1 is overlayed on observational data from Shores et al. showing the relationship between serum DHT and incident cardiovascular disease risk. The solid line represents the estimated hazard ratio (HR) and the shaded area depicts the 95% confidence intervals. All models are adjusted for age. (Reprinted with permission from Shores et al. J Clin Endocrinol Metab 2014, 99:2061-2068. [23]). DHT, dihydrotestosterone; RCT, randomized controlled trial.

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Source: PubMed

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