Conclusions Oral TRT produces significant CV risk .
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
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 .
Decline of plasma 5α‐dihydrotestosterone (DHT) levels upon testosterone administration to elderly men with subnormal plasma testosterone and high DHT levels
The study was performed to measure the impact of testosterone ( T ) administration on circulating levels of 5α‐dihydrotestosterone ( DHT ) .  Group 1 ( 32 men ; mean age 61 years ; mean T 6.9 ± 1.9 nmol l−1 ) were treated for 15 months with long‐acting T undecanoate .  Group 2 ( 23 men , mean age 60 years , mean T 7.6 ± 2.0 nmol l−1 ) were treated for 9 months with T gel  . Plasma T and DHT were measured before and after 9 months T administration . In the men treated with T undecanoate  plasma T and DHT were also measured after 12 and 15 months . Before T administration , plasma DHT ranged from 0.39 to 1.76 nmol l−1 ( 0.30–1.90 nmol l−1 ) . Mean DHT declined upon T administration from 0.95 ± 0.50 to 0.55 ± 0.30 nmol l−1 ( P < 0.05 ) . With an arbitrary cut‐off at 0.60 nmol l−1 , all 21 values of DHT > 0.60 nmol l−1 had fallen from 1.29 ± 0.50 to 0.70 ± 0.60 nmol l−1 ( P < 0.01 ) . Below this cut‐off point 13 values rose and 21 fell upon T administration . Below this cut‐off point values on average declined from 0.39 ± 0.12 to 0.30 ± 0.14 nmol l−1 ( P < 0.05 ) . The study revealed that in a cohort  of elderly men with subnormal plasma T levels plasma DHT levels declined upon T administration when they were in the higher range of normal ( > 0.6 nmol l−1 ) , with a profound shift of DHT/T ratios presumed to be an indicator of a reduced 5α‐reductase activity . Below plasma DHT levels of 0.6 nmol l−1 , responses of plasma DHT to T administration varied
Conclusions Oral TRT produces significant CV risk .
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
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 .