Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men.
None of the current or experimental androgen treatment modalities for male hypogonadism has been reported to produce physiological concentrations or circadian variations in testosterone (T) and its metabolites, dihydrotestosterone (DHT) and estradiol (E2). This investigation describes a novel transdermal dosage form designed to enhance the delivery of native T across nonscrotal skin. The main objective was to determine whether the nightly application of two experimental transdermal patches to different sites on the body (e.g. back, chest, arms, etc.) would result in normal plasma levels of T, DHT, and E2 for men and mimic the normal circadian variation. Six hypogonadal males (aged 24-66 yr) were studied 4 weeks after stopping T ester treatment. After single application of two patches, T levels increased from a pretreatment baseline of 5.8 +/- 0.94 nmol/L (mean +/- SE; 167 +/- 27 ng/dL) to an average peak concentration of 44.1 +/- 4.8 nmol/L (1273 +/- 138 ng/dL) 5.7 +/- 0.6 h after application and reached a 24-h level of 16.9 +/- 2.9 nmol/L (488 +/- 85 ng/dL). DHT and E2 levels exhibited parallel variations within the normal reference ranges. During 4 weeks of daily evening application to various sites on the torso, the mean delivery of T from two patches was 5.2 +/- 0.1 mg/day (approximately 20% of the patch content), and morning T levels were within the normal limits. On day 28 of treatment, the 24-h plasma profiles of T, DHT, and E2 (obtained with two patches on the back) approximately mimicked the normal circadian variations reported in healthy young men. The time-averaged T level was 21.8 +/- 2.9 nmol/L (629 +/- 84 ng/dL), and the plasma concentration ratios of DHT/T (0.07 +/- 0.01) and E2/T (0.005 +/- 0.001) were within the normal range. SHBG concentrations were not significantly altered over the 4 weeks of treatment. The patches were well tolerated, except for one patient who developed a local reaction to an excipient during the third week of treatment. Two of the patients (one with Klinefelter's syndrome) completed several months of continuous therapy. T, DHT, and E2 have remained in the range of normal, and plasma LH levels in the patient with Klinefelter's syndrome became normal. Subjective improvement in symptoms has continued, and tolerability has been good in both patients. These results indicate that the enhanced transdermal delivery of T across nonscrotal skin is a patient-friendly androgen replacement modality and produces physiological concentrations of T and its metabolites, which are unattainable with other treatment modalities.
Meikle
A W
AW
Department of Medicine, University of Utah, Salt Lake City.
Mazer
N A
NA
Moellmer
J F
JF
Stringham
J D
JD
Tolman
K G
KG
Sanders
S W
SW
Odell
W D
WD
D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D013196:Dihydrotestosterone / Q000097:blood; D004958:Estradiol / Q000097:blood; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy* / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013739:Testosterone / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use
D012738:Sex Hormone-Binding Globulin; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone