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 .
Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study.
Testosterone ( T ) in a hydroalcoholic gel has been developed as an effective and convenient open system for transdermal delivery of the hormone to men . Because the gel can be applied either to small or large areas of skin , it was important to assess whether the skin surface area on which the gel was applied was an important determinant of serum T levels . To answer this question , the pharmacokinetics of a transdermal 1 % hydroalcoholic gel preparation of T was studied in nine hypogonadal men . The subjects applied in r and om order a 25-mg metered dose of T gel either four times at one site ( left arm/shoulder ) or at four different sites ( left and right arms/shoulders and left and right abdomen ) once daily ( 6 - 8 min ) for 7 consecutive days . After 7 days of washout , each subject was then crossed over to the opposite regimen for another 7 days of treatment . Serum sample s were collected for measurements of T , 5alpha dihydrotestosterone ( DHT ) , and estradiol before , during ( days 1 , 2 , 3 , 5 , and 7 ) , and after ( days 8 , 9 , 11 , 13 , and 15 ) application of T gel . Multiple blood sample s were drawn on the 1st and 7th day after gel application ; single sample s were obtained just before the next T gel application on other days ( 24 h after the previous gel application ) . The T gel dried in less than 5 min , left no residue , and produced no skin irritation in any of the subjects . Mean serum T levels , irrespective of application at one site or four sites followed the same pattern : rising to 2- to 3- and 4- to 5-fold above baseline at 0.5 and 24 h after first application , respectively . Thereafter , serum T levels reached steady state and remained at 4- to 5-fold above baseline ( at the upper limit of the normal adult range ) for the duration of gel application and returned to baseline within 4 days after stopping application . The application of T gel at four sites ( application skin area approximately four times that of one site ) result ed in a mean area under the curve ( AUC0 - 24h ) for serum T levels on the 7th day ( 868 + /- 72 nmol*h/L , mean + /- SEM ) , which was 23 % higher but not significantly different ( P = 0.06 ) than repeated application at one site ( 706 + /- 59 nmol*h/L ) . This could be due to the limited number of subjects studied ( n = 9 ) .  Mean serum DHT levels followed the same pattern as serum T , achieving steady-state levels by 2 days . The mean concentration of serum DHT on the 7th day was significantly higher after application at four sites ( 9.15 + /- 1.26 nmol/L , P < 0.05 ) than at one site ( 6.9 + /- 0.77 nmol/L ) . These serum DHT levels were at or above the normal adult male range . Serum DHT : T ratio was not significantly altered by T gel application . Serum estradiol levels followed the same pattern as serum T and showed no significant difference between the one- or four-site application . We conclude that transdermal daily application of 100 mg T gel result ed in similar steady levels of serum T. The surface area of the skin to which the gel was applied had only a modest impact on serum T and DHT levels . Mean serum levels of T and DHT was higher by 23 % and 33 % , respectively , despite application of the gel to four times the skin area in the four sites compared with the one site group . Because of the greater dosage flexibility provided , hydroalcoholic T gel application over multiple sites seems to be an effective and nonskin-irritating method of transdermal T delivery for hypogonadal men . Dose-ranging studies are required to determine dosage regimens for T gel application as a replacement therapy in hypogonadal men
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 .