Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men.

OBJECTIVE: An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeation-enhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12-month period.

DESIGN: Open-label, multicentre study with four consecutive periods: Period I (3 weeks)--evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)--androgen washout; Period III (3-4 weeks)--single-dose pharmacokinetic studies of TTD systems; Period IV (12 months)--efficacy, safety, and steady-state pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared.

PATIENTS: Thirty-seven hypogonadal men 21-65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three).

MEASUREMENTS: Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E2) levels. Circadian pattern of T profiles and 24-hour time-average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters.

RESULTS: Twelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24-hour time-average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2-4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate-specific antigen level during TTD therapy compared to IM injections (0.66 vs 1.00 microgram/l P < 0.001), while prostate size did not differ significantly between the two treatment regimens.

CONCLUSIONS: The permeation-enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.