Transdermal application

The skin easily absorbs steroids and other drugs and transdermal drug delivery has become a widely used therapeutic modality. The scrotum shows the highest rate of steroid absorption, about 40-fold higher than the forearm (Feldmann and Maibach 1967). This difference in absorption rates has been exploited for the development of a transdermal therapeutic system (TTS) to deliver testosterone. 40 and 60 cm2 large polymeric membranes loaded with 10 or 15 mg testosterone when attached to the scrotal skin deliver sufficient amounts of the steroid to provide hypogonadal men with serum levels in the physiological range (Bals-Pratsch et al. 1986; 1988; Findlay et al. 1987; Korenmann et al. 1987). The application of the patch to scro-tal skin requires hair clipping or shaving to optimize adherence. The membranes need to be renewed every day. When applied in the morning and worn until the next morning the resulting serum testosterone levels resemble the normal diurnal variations of serum testosterone in normal men without supraphysiological peaks (Bals-Pratsch et al. 1988). Long-term therapy up to ten years with daily administration of the scrotal patch in 11 hypogonadal men produced steady-state serum levels of testosterone and estradiol in the normal range and serum levels of DHT at or slightly above the higher limit of normal without significant adverse side-effects (Fig. 14.16) (Behre etal. 1999b).

While testosterone is readily absorbed by genital skin, transdermal systems for use on non-genital skin require enhancers to facilitate sufficient testosterone passage through the skin. The permeation enhanced testosterone patch delivers 2.5 mg/day testosterone when applied to non-scrotal skin. If one or two such systems are worn for 24 hours physiologic serum testosterone levels can be mimicked, as with scrotal patches (Fig. 14.17) (Brocks etal. 1996; Meikle etal. 1996). Due to the alcoholic enhancer used and the occlusive nature of the systems, the application is associated with skin irritation in up to 60% of the subjects, with most users discontinuing

Q 25

Time (years)

Fig. 14.16 Serum concentrations (mean ± SEM) of testosterone (squares) and DHT (circles) in 11 hypogonadal men before and during treatment with transscrotal testosterone patches. Broken lines indicate normal range of testosterone, dotted line upper normal limit of DHT (adapted with permission from Behre etal. 1999b, copyright 1999, Blackwell Publishing).

Fig. 14.17 Serum concentrations (mean ± SD) of testosterone during and after nighttime application of two non-scrotal testosterone systems to the backs of 34 hypogonadal men. Shaded area indicates normal range of testosterone (adapted with permission from Meikle etal. 1996, copyright 1996, The Endocrine Society).

Fig. 14.17 Serum concentrations (mean ± SD) of testosterone during and after nighttime application of two non-scrotal testosterone systems to the backs of 34 hypogonadal men. Shaded area indicates normal range of testosterone (adapted with permission from Meikle etal. 1996, copyright 1996, The Endocrine Society).

application because of the skin irritation (Jordan 1997; Parker and Armitage 1999). Preapplication ofcorticosteroid cream to the skin has been reported to decrease the severity of skin irritation, although the effects on pharmacokinetics of testosterone are unclear. Another larger non-scrotal patch causes less skin irritation (about 12% itching and 3% erythema) but may create adherence problems (Jordan etal. 1998).

Nevertheless, both transdermal modalities through either scrotal or non-genital skin provide physiologic serum testosterone levels and have been shown to reverse the signs and symptoms of male hypogonadism with only minor systemic side-effects (Behre etal. 1999b; Dobs etal. 1999).

In 2000, a 1% colourless hydroalcoholic gel containing 25 or 50 mg testosterone in 2.5 or 5 g gel was approved for clinical use in hypogonadism. The gel dries in less than 5 min without leaving a visible residue on the skin. About 9 to 14% of the testosterone in the gel is bioavailable. Application of the testosterone gel increased serum testosterone levels into the normal range within one hour after application (Wang etal. 2000). Steady-state serum levels are achieved 48-72 hours after initiation of therapy, whereas pre-treatment serum testosterone levels are seen four days after stopping application. The application of the testosterone gel at four sites (application skin areas approximately four times that of one site) resulted in an area under the curve of testosterone which was 23% higher compared to application of the same amount of gel on one site. However, this difference did not achieve statistical significance in the nine hypogonadal men tested (Wang etal. 2000).

Long-term pharmacokinetics of the transdermal testosterone gel were evaluated in 227 hypogonadal men (Swerdloff etal. 2000). Patients were randomly assigned to application of 5 or 10 g of the testosterone gel or two patches of a non-scrotal testosterone system. After 90 days of testosterone gel treatment, the dose was titrated up (5 to 7.5 g) or down (10 to 7.5 g) if the preapplication serum testosterone levels were outside the normal adult male range. During long-term treatment mean serum levels of testosterone were maintained in the mid normal range with 5 g of gel and in the upper normal range with 10 g of gel (Fig. 14.18). Testosterone gel application resulted in dose-proportionate increases in serum DHT and E2 as well as dose-proportionate decreases of gonadotropins.

The advantages of the testosterone gel over the testosterone patch are a lower incidence of skin irritation, the ease of application, the invisibility of the dried gel, and the ability to deliver testosterone dose-dependently to the low, mid or upper normal range. A potential adverse side-effect of testosterone gel application is the transfer of testosterone to women or children upon close contact with the skin. Transfer of transdermal testosterone from the skin can be avoided by applying gel to skin covered by clothing or showering after application. This preparation has gained a significant market share of androgen formulations in Europe and the United States, although it is marketed at a slightly higher price than the patches and at a much higher price than injectable testosterone.

Currently, a number of other testosterone gels and creams are being developed. Two recent randomized controlled studies demonstrated a dose-dependent increase

Testosteron Patch

Fig. 14.18

Serum concentrations (mean ± SEM) of testosterone before (day 0) and after transdermal testosterone applications on days 1, 30, 90, and 180. Time 0 was 0800 h, when blood sampling usually began. On day 90, the dose in the subjects applying testosterone gel 50 or 100 mg was up- or down-titrated if their preapplicaton serum testosterone levels were below or above the normal adult male range, respectively. Dotted lines denote the adult normal range (adapted with permission from Swerdolff et al. 2000, copyright 2000, The Endocrine Society).

0 8 16 Time(hours)

Fig. 14.18

Serum concentrations (mean ± SEM) of testosterone before (day 0) and after transdermal testosterone applications on days 1, 30, 90, and 180. Time 0 was 0800 h, when blood sampling usually began. On day 90, the dose in the subjects applying testosterone gel 50 or 100 mg was up- or down-titrated if their preapplicaton serum testosterone levels were below or above the normal adult male range, respectively. Dotted lines denote the adult normal range (adapted with permission from Swerdolff et al. 2000, copyright 2000, The Endocrine Society).

of testosterone serum levels to the normal range in hypogonadal men after 90 days of application of 5 g/d or 10 g/d of another hydroalcoholic topical gel containing 1% testosterone compared to non-scrotal testosterone patches (n = 208, McNicholas et al. 2003) or compared to non-scrotal testosterone patches and placebo gel (n = 406, Steidle etal. 2003). Application of5g/d ofa2.5% hydroalcoholic gel increased serum levels of testosterone to the normal range in 14 gonadotropin-suppressed normal men (Rolf et al. 2002a). Washing of the skin after 10 min. did not influence the pharmacokinetic profile. No interpersonal testosterone transfer could be detected after evaporation of the alcohol vehicle of this testosterone gel (Rolf etal. 2002b). This gel preparation can also be administered at a dose of 1 g/d to the scrotal skin. Ongoing randomized controlled studies in hypogonadal patients indicate the efficacy and practicability of administration of this gel to normal or scrotal skin.

14.4 Key messages

• Oral, buccal, injectable, subdermal implantable and transdermal testosterone preparations are available for clinical use. The best preparation is the one that replaces testosterone serum levels at as close to physiologic concentrations as possible.

• Oral administration of the currently available testosterone undecanoate preparation results in high interindividual and intraindividual variability of serum testosterone values.

• Daily or twice daily buccal administration of testosterone tablets increases serum testosterone to the normal range. Acceptability of this application form has yet to be determined.

• The available testosterone esters for intramuscular injection (testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone cyclohexanecarboxylate) are still widely used but suboptimal for the treatment of male hypogonadism. Doses and injection intervals most frequently used in the clinic lead to initial supraphysiological testosterone levels and subnormal values before the next injection. To obtain testosterone serum concentrations continuously in the normal range, unacceptably frequent small doses would have to be injected.

• Intramuscular injection of 1000 mg testosterone undecanoate to hypogonadal men maintains serum levels of testosterone within the normal range for up to 12 weeks. Recently approved for clinical use, intramuscular testosterone undecanoate will become a valuable preparation for depot substitution therapy of male hypogonadism and for male contraception.

• A single implantation procedure of testosterone pellets provides serum levels of testosterone in the normal range for up to six months. Pellet extrusion occurs in about 10% of the implantation procedures. Due to the long-lasting effect and the inconvenience of removal, preferably pellets should be used by men in whom the beneficial effects and tolerance for androgen replacement therapy have already been established.

• Subcutaneous injection of testosterone microcapsules in hypogonadal men increases serum testosterone levels to the normal range for five to seven weeks. One disadvantage of the testosterone microcapsules formulation seems to be the early burst release of testosterone.

• Transdermal application of testosterone by scrotal or non-scrotal patches increases serum levels of testosterone to the normal range and even mimics the physiological circadian testosterone rhythm. Non-scrotal testosterone patches cause skin irritations in up to 60% of patients, or might have adherence problems.

• Daily administration of testosterone gel increases serum levels of testosterone in hypogonadal patients dose-dependently to the normal range. Acceptability of the gel is high and it has become a standard replacement therapy within the first years following its approval.


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