title: Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis.
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.
authors.affiliation: Geriatric Research, Education and Clinical Center, Malcom Randall VA Medical Center, 1601 SW Archer RD, Gainesville 32605-1197, FL, USA. Stephen.borst@va.gov.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Borst
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Shuster
authors.forename: Baiming
authors.initials: B
authors.lastname: Zou
authors.forename: Fan
authors.initials: F
authors.lastname: Ye
authors.forename: Huanguang
authors.initials: H
authors.lastname: Jia
authors.forename: Anita
authors.initials: A
authors.lastname: Wokhlu
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Yarrow
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology*; D013196:Dihydrotestosterone / Q000097:blood*; D020249:Hormone Replacement Therapy; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013739:Testosterone / Q000008:administration & dosage*
chemical_list: D013196:Dihydrotestosterone; D013739:Testosterone