In a steady-state study of 12 hypogonadal men, nightly application of 1, 2, or 3 Androderm 2.5 mg systems resulted in increases in the mean morning serum testosterone concentrations. These concentrations averaged 424,584, and 766 ng/dL with the application of 1, 2, and 3 systems, respectively. The mean baseline serum testosterone concentration was 76 ng/dL.

Normal range morning serum testosterone concentrations are reached during the first day of dosing. There is no accumulation of testosterone during continuous treatment. In a study of 20 hypogonadal patients, two Androderm 2.5 mg systems and a single Androderm 5 mg system produced equivalent serum testosterone concentration profiles.

Average steady state concentrations over 24 hours (C_ssavg) were 613±169 and 621±176 ng/dL for the two 2.5 mg and single 5 mg systems, respectively. C_max values were 925±340 ng/dL for the two 2.5 mg systems and 905±254 ng/dL for the single 5 mg system.

In 16 hypogonadal men, the topical. administration of 0.1% triamcinolone cream to the skin under the central drug reservoir prior to application of the Androderm system did not significantly alter transdermal absorption of testosterone; however, the rate of complete adherence was lower. In these patients, pretreatment with an ointment formulation significantly reduced testosterone absorption from the system.

In serum, testosterone is bound with high affinity to sex hormone binding globulin (SHBG) and with low affinity to albumin. The albumin bound portion easily dissociates and is presumed to be bioactive. The SHBG-bound portion is not considered to be bioactive. The amount of SHBG in serum and the total testosterone concentration determine the distribution of bioactive and non-bioactive androgen.

Bioactive serum testosterone concentrations (BT) measured during Androderm (testosterone transdermal system) treatment paralleled the serum testosterone profile (Figure 2) and remained within the normal reference range.

Inactivation of testosterone occurs primarily in the liver. Testosterone (T) is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol (E₂) and dihydrotestosterone (DHT). DHT binds with greater affinity to SHBG than does testosterone. In reproductive tissues, DHT is further metabolized to 3-alpha and 3-beta androstanediol.

In many tissues, the activity of testosterone appears to depend on reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus, where it initiates transcription events and cellular changes related to androgen action.

During steady-state pharmacokinetic studies in hypogonadal men treated with Androderm, the average DHT:T and E2:T ratios were comparable to those in normal men, approximately 1:10 and 1:200, respectively.

Upon removal of the Androderm systems, serum testosterone concentrations decrease with an apparent half-life of approximately 70 minutes. Hypogonadal concentrations are reached within 24 hours following system removal.

Androderm therapy suppresses endogenous testosterone secretion via the pituitary/gonadal axis, resulting in a reduction in baseline serum testosterone concentrations compared to the untreated state.

Approximately 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronide and sulfate conjugates of testosterone and its metabolites; about 6% is excreted in the feces, mostly in unconjugated form.

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