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.

14.5 REFERENCES

Aakvaag A, Stromme SB (1974) The effect of mesterolone administration to normal men on the pituitary-testicular function. Acta Endocrinol 77:380-386 Alkalay D, Khemani L, Wagner WE, Bartlett MF (1973) Sublingual and oral administration of methyltestosterone. A comparison of drug bioavailability. J Clin Pharmac 13:142-151

Amory JK, Anawalt BD, Blaskovich PD, Gilchriest J, Nuwayser ES, Matsumoto AM (2002) Testosterone release from a subcutaneous, biodegradable microcapsule formulation (Viatrel) in hypogonadal men. J Androl 23:84-91 Anderson RA, Wallace AM, Sattar N, Kumar N, Sundaram K (2003) Evidence for tissue selectivity of the synthetic androgen 7alpha-methyl-19-nortestosterone in hypogonadal men. J Clin Endocrinol Metab 88:2784-2793 Anderson RA, Wu FC (1996) Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. II. Pharmacokinetics and pharmacodynamics of once weekly administration of testosterone enanthate. J Clin Endocrinol Metab 81:896-901

Anderson RA, Zhu H, Cheng L, Baird DT (2002) Investigation of a novel preparation of testosterone decanoate in men: pharmacokinetics and spermatogenic suppression with etonogestrel implants. Contraception 66:357-364 Asch RH, Heitman TO, Gilley RM, Tice TR (1986) Preliminary results on the effects oftestosterone microcapsules. In: Zatuchni GI, Goldsmith A, Spieler JM, Sciarra JJ (eds) Male contraception: advances and future prospects, Harper & Row, Philadelphia, pp 347-360 Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS (2003) Important effect of food on the bioavailability of oral testosterone undecanoate. Pharmacotherapy 23:319-325 Baisley KJ, Boyce MJ, Bukofzer S, Pradhan R, Warrington SJ (2002) Pharmacokinetics, safety and tolerability of three dosage regimens of buccal adhesive testosterone tablets in healthy men suppressed with leuprorelin. J Endocrinol 175:813-819 Bals-Pratsch M, Knuth UA, Yoon YD, Nieschlag E (1986) Transdermal testosterone substitution therapy for male hypogonadism. Lancet ii:943-946 Bals-Pratsch M, Langer K, Place VA, Nieschlag E (1988) Substitution therapy of hypogonadal men with transdermal testosterone over one year. Acta Endocrinol (Copenh) 118:7-13 Behre HM, Nieschlag E (1992) Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab 75:1204-1210

Behre HM, BausS, KlieschS, Keck C, SimoniM, Nieschlag E (1995) Potential oftestosterone buci-clate for male contraception: endocrine differences between responders and nonresponders. J Clin Endocrinol Metab 80:2394-2403 Behre HM, Abshagen K, Oettel M, Hubler D, Nieschlag E (1999a) Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur J Endocrinol 140:414-419 Behre HM, von Eckardstein S, Kliesch S, Nieschlag E (1999b) Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7-10 years. Clin Endocrinol (Oxf) 50:629-635

Berthold AA (1849) Transplantation der Hoden. Archiv fur Anatomie, Physiologie und wissenschaftliche Medicin, Berlin, 42-46 Bhasin S, Swerdloff RS, Steiner B, Peterson MA, Meridores T, Galmirini M, Pandian MR, Goldberg R, Berman N (1992) A biodegradable testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for 10-11 weeks in hypgonadal men. J Clin Endocrin Metab 74:75-83

Bird D, Vowles K, Anthony PP (1979) Spontaneous rupture of a liver cell adenoma after long term methyltestosterone: report of a case successfully treated by emergency right hepatic lobetomy. Br J Surg 66:212-213

Boyd PR, Mark GJ (1977) Multiple hepatic adenomas and a heptatocellular carcinoma in a man on oral methyl testosterone for eleven years. Cancer 40:1765-1770 Breuer H, Gutgemann D (1966) Wirkung von 1alpha-Methyl-5alpha-androstan-17ß-ol-3-on (Mesterolon) auf die Steroidausscheidung beim Menschen. Arzneimittelforschung 16:759762

Brocks DR, Meikle AW, Boike SC, Mazer NA, Zariffa N, Audet PR, Jorkasky DK (1996) Pharmacokinetics of testosterone in hypogonadal men after transdermal delivery: influence of dose. J Clin Pharmacol 36:732-739 Brown-Sequard CE (1889) Des effets produits chez l'homme par des injections souscutanees d'un liquide retire des testicules frais de cobaye et de chien. C R Seanc Soc Biol 1:420-430 Burris AS, Ewing LL, Sherins RJ (1988) Initial trial of slow-release testosterone microspheres in hypogonadal men. Fertil Steril 50:493-497 Butenandt A (1931) Über die chemische Untersuchung des Sexualhormons. Z Angew Chem 44:905-908

Butenandt A, Hanisch G (1935) Über Testosteron. Umwandlung des Dehydroandrosterons in Androstendiol und Testosteron; ein Weg zur Darstellung des Testosterons aus Cholesterin. Hoppe-Seyler's Z Physiol Chem 237:89-98 Cantrill AJ, Dewis P, Large DM, Newman M, Anderson DC (1984) Which testosterone replacement therapy? Clin Endocrinol 21:97-107 Carbone JV, Grodsky GM, Hjelte V (1959) Effect of hepatic dysfunction on circulating levels of sulphobromopthalein and its metabolites. J Clin Invest 38:1989-1996 Coert A, Geelen J, de Visser J, van der Vies J (1975) The pharmacology and metabolism of testosterone undecanoate (TU), a new orally active androgen. Acta Endocrinol 79:789800

Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ (1988) Randomized clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 11:247-264 Coombes GB, Reiser J, Paradinas FJ, Burn I (1978) An androgen-associated hepatic adenoma in a trans-sexual. Br J Surg 65:869-870 Crabbe P, Diczfalusy E, Djerassi C (1980) Injectable contraceptive synthesis: an example of international cooperation. Science 209:992-994 Cunningham GR, Silverman VE, Kohler PO (1978) Clinical evaluation of testosterone enan-thate for induction and maintenance of reversible azoospermia in man. In: Patanelli DJ (ed) Hormonal control of male fertility. Department of Health, Education and Welfare. National Institutes of Health, Bethesda, Md, Publ No (NIH) 78-1097, pp 71-87 Cussons AJ, Bhagat CI, Fletcher SJ, Walsh JP (2002) Brown-Sequard revisited: a lesson from history on the placebo effect of androgen treatment. Med J Aust 177:678-679 Daggett PR, Wheeler MJ, Nabarro JDN (1978) Oral testosterone: a reappraisal. Horm Res 9:121129

Danner C, Frick G (1980) Androgen substitution with testosterone-containing nasal drops. Int J Androl 3:429-431

David K, Dingemanse E, Freud J, Laquer E (1935) Über kristallinisches männliches Hormon aus Hoden (Testosteron), wirksamer als aus Harn oder aus Cholesterin bereitetes Androsteron. Hoppe-Seyler's Z physiol Chem 233:281-282 Deansley R, Parkes AS (1938) Further experiments on the administration of hormones by the subcutaneous implantation of tablets. Lancet ii:606-608 de Lorimer AA, Gordan GS, Lowe RC, Carbone JV (1965) Methyltestosterone: related steroids and liver function. Arch Intern Med 116:289-294 Dobs AS, Hoover DR, Chen MC, Allen R (1998) Pharmacokinetic characteristics, efficacy, and safety of buccal testosterone in hypogonadal males: a pilot study. J Clin Endocrinol Metab 83:33-39

Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA (1999) Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab 84:3469-3478 Escamilla RF (1949) Treatment of preadolescent eunuchoidism with (methyl)testosterone linguets. Amer Pract 3:425 Falk H, Thomas LB, Popper H, Ishak KG (1979) Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet ii:1120-1123 Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H (1975) Androgen-induced hepatoma. Lancet i:430-432 Feldmann RJ, Maibach HI (1967) Regional variation in percutaneous penetration of 14C cortisol in man. J Invest Dermatol 48:181-183 Findlay JC, Place VA, Snyder PJ (1987) Transdermal delivery of testosterone. J Clin Endocrinol Metab 64:266-268

Frey H, Aakvaag A, Saanum D, Falch J (1979) Bioavailability of oral testosterone in males. Eur J

Clin Pharmacol 16:345-349 Fujioka M, Shinohara Y, Baba S, Irie M, Inoue K (1986) Pharmacokinetic properties of testosterone propionate in normal men. J Clin Endocrinol Metab 63:1361-1364 Fukutani K, Isurugi K, Takayasu H, Wakabayashi K, Tamaoki B-I (1974) Effects of depot testosterone therapy on serum levels of luteinizing hormone and follicle-stimulating hormone in patients with Klinefelter's syndrome and hypogonadotropic eunuchoidism. J Clin Endocrinol Metab 39:856-864

Gardner FH, Besa EC (1983) Physiologic mechanisms and the hematopoietic effects of the androstanes and their derivatives. Curr Top Hematol 4:123-195 Gerhards E, Gibian H, Kolb KH (1966) Zum Stoffwechsel von 1alpha-Methyl-5alpha androstan-

17ß-ol-3-on (Mesterolon) beim Menschen. Arneimittelforschung 16:458-463 Goodman MA, Laden AMJ (1977) Hepatocellular carcinoma in association with androgen therapy. Med J Aust i:220-221 Gordon RD, Thomas MJ, Poyntin JM, Stocks AE (1975) Effect of mesterolone on plasma LH,

FSH and testosterone. Andrologia 7:287-296 Gu YQ, WangXH, Xu D, Peng L, Cheng LF, Huang MK, Huang ZJ, Zhang GY (2003) A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab 88:562-568

Hamburger C (1958) Testosterone treatment and 17-ketosteroid excretion. Acta Endocrinol 28:529-536

Handelsman DJ, Conway AJ, Boylan LM (1990) Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 70:216-222 Handelsman DJ, Mackey MA, Howe C, Turner L, Conway AJ (1997) Analysis of testosterone implants for androgen replacement therapy. Clin Endocrinol 47:311-316 Heywood R, Hunter B, Green OP, Kennedy SJ (1977a) The toxicity of methyl testosterone in the rat. Toxicology Letters 1:27-31 Heywood R, Chesterman H, Ball SA, Wadsworth PF (1977b) Toxicity of methyl testosterone in the beagle dog. Toxicology 7:357-365 Horst HJ, Holtge WJ, Dennis M, Coert A, Geelen J, Voigt KD (1976) Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man. Klin Wschr 54: 875-879

Jockenhovel F, Vogel E, Kreutzer E, Reinhard W, Lederbogen S, Reinwein D (1996) Pharmacoki-netics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal man. Clin Endocrinol 45:61-71 Johnsen SG (1978) Long-term androgen therapy with oral testosterone. In: Patanelli DJ (ed) Hormonal control of male fertility. DHEW publication No (NIH) 78-1097. Bethesda, pp 123-143

Johnsen SG, Bennet EP, Jensen VG (1974) Therapeutic effectiveness of oral testosterone. Lancet 2:1473-1475

Johnsen SG, Kampmann JP, Bennet EP, Jörgensen F (1976) Enzyme induction by oral testosterone. Clin Pharmacol Ther 20:233-237 Jordan WP (1997) Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems. Am J Cont Dermat 8:108-113

Jordan WP, Atkinson LE, Lai C (1998) Comparison of the skin irritation potential of two testosterone transdermal systems: an investigational system and a marketed product. Clin Ther 20:80-87.

Junkmann K (1952) Über protrahiert wirksame Androgene. Arch Path Pharmacol 215:85-92 Junkmann K (1957) Long-acting steroids in reproduction. Rec Progr Horm Res 13:389-419 Kelleher S, Conway AJ, Handelsman DJ (1999) A randomized controlled clinical trial of antibiotic impregnation of testosterone pellet implants to reduce extrusion rate. Eur J Endocrinol 146:513-518

Kelleher S, Conway AJ, Handelsman DJ (2001) Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants. Clin Endocrinol (Oxf) 55:531-536

Kopera H (1985) The history of anabolic steroids and a review of clinical experience with anabolic steroids. In: Eikelboom FA, van der Vies J (eds) Anabolics in the '80s. Acta endocrinol suppl 271:11-18

Korenman SG, Viosca S, Garza D, Guralnik M, Place V, Campbell P, Stanik Davis S (1987) Androgen therapy of hypogonadal men with transscrotal testosterone system. Am J Med 83:471-478

Krüskemper HI, Noell G (1967) Steroidstruktur und Lebertoxizität. Acta endocrinol 54:73-80 Loewe S, Voss HE (1930) Der Standder Erfassung des männlichen Sexualhormons (Androkinins). KlinWschr 9:481-487

Maisey NM, Bingham J, Marks V, English J, ChakrabortyJ (1981) Clinical efficacy oftestosterone undecanoate in male hypogonadism. Clin Endocrinol 14:625-629 Mackey MA, Conway AJ, Handelsman DJ (1995) Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod 10:862-865 Mazer NA, Heiber WE, Moellmer JF, Meikle AW, Stringham JD, Sanders SW, Tolman KG, Odell WD (1992) Enhanced transdermal delivery of testosterone: a new physiological approach for androgen replacement in hypogonadal men. J Control Release 19:347-362 McCaughan GW, Bilous MJ, Gallagher ND (1985) Long-term survival with tumor regression in androgen-induced liver tumors. Cancer 56:2622-2626 McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA (2003) A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 91:69-74 Meikle AW, Arver S, Dobs AS, Sanders SW, Rajaram L, Mazer N (1996) Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site - a clinical research center study. J Clin Endocrinol Metab 81:18321840

Methyltestosteron-Monographie (Anonymous) (1988) Bundesanzeiger 40:5140-5141 Minto CF, Howe C, Wishart S, Conway AJ, Handelsman DJ (1997). Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and injection volume. J Pharmacol Exp Ther 281:93-102 Nankin HR (1987) Hormone kinetics after intramuscular testosterone cypionate. Fertil Steril 47:1004-1009

Nieschlag E (1981) Ist die Anwendung von Methyltestosteron obsolet? Dtsch med Wschr 106:1123-1125

Nieschlag E, Mauss J, Coert A, Kicovic P (1975) Plasma androgen levels in men after oral administration oftestosterone or testosterone undecanoate. Acta endocrinol 79:366-374 Nieschlag E, Cuppers HJ, Wiegelmann W, Wickings EJ (1976) Bioavailability and LH-suppressing effect of different testosterone preparations in normal and hypogonadal men. Horm Res 7:138145

Nieschlag E, Cuppers EJ, Wickings EJ (1977) Influence of sex, testicular development and liver function on the bioavailability of oral testosterone. Euro J Clin Invest 7:145-147 Nieschlag E, Buchter D, von Eckardstein S, Abshagen K, Simoni M, Behre HM (1999) Repeated intramuscular injections oftestosterone undecanoate for substitution therapy in hypogonadal men. Clin Endocrinol (Oxf) 51:757-763 Paradinas FJ, Bull TB, Westaby D, Murray-Lyon IM (1977) Hyperplasia and prolapse of hepa-tocytes into hepatic veins during longterm methyltestosterone therapy: possible relationships of these changes to the development of peliosis hepatis and liver tumours. Histopathology 1:225-246

Parker S, Armitage M (1999) Experience with transdermal testosterone replacement therapy for hypogonadal men. Clin Endocrinol (Oxf) 50:57-62

Partsch CJ, Weinbauer GF, Fang R, Nieschlag E (1995) Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate. Eur J Endocrinol 132:514-519 Pitha J, Harman SM, Michel ME (1986) Hydrophilic cyclodextrin derivatives enable effective oral administration of steroidal hormones. J Pharm Sci 75:165-167 Rajalakshmi M, Ramakrinshnan PR (1989) Pharmacokinetics and pharmacodynamics of a new long-acting androgen ester: maintenance of physiological androgen levels for 4 months after a single injection. Contraception 40:399-412 Rolf C, Kemper S, Lemmnitz G, Eickenberg U, Nieschlag E (2002a) Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men. Eur J Endocrinol 146:673-679

RolfC, KnieU, Lemmnitz G, Nieschlag E (2002b) Interpersonal testosterone transfer after topical application of a newly developed testosterone gel preparation. Clin Endocrinol (Oxf) 56:637641

Ruzicka L, Wettstein A (1935) Synthetische Darstellung des Testishormons, Testosteron

(Androsten 3-on-17-ol). Helv chim Acta 18:1264-1275 Ruzicka L, Goldberg MW, Rosenberg HR (1935) Herstellung des 17a-Methyl- testosterons und anderer Androsten- und Androstanderivate. Zusammenhange zwischen chemischer Konstitution und mannlicher Hormonwirkung. Helv Chim Acta 18:1487-1498 Salehian B, Wang C, Alexander G, Davidson T, McDonald V, Berman N, Dudley RE, Ziel F, Swerdloff RS (1995) Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate - a clinical research center study. J Clin Endocrinol Metab 80:3567-3575 Schulte-Beerbuhl M, Nieschlag E (1980) Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate or testosterone cypionate. Fertil Steril 33:201-203 Schurmeyer T, Nieschlag E (1984) Comparative pharmacokinetics of testosterone enanthate and testosterone cyclohexanecarboxylate as assessed by serum and salivary testosterone levels in normal men. Int J Androl 7:181-187 Schurmeyer T, Wickings EJ, Freischem CW, Nieschlag E (1983) Saliva and serum testosterone following oral testosterone undecanoate administration in normal and hypogonadal men. Acta endocrinol 102:456-462 Shackleford DM, Faassen WA, Houwing N, Lass H, Edwards GA, Porter CJ, Charman WN (2003) Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two Andriol formulations in conscious lymph duct-cannulated dogs. J Pharmacol Exp Ther 306:925-933 Simmer H, Simmer I (1961) Arnold Adolph Berthold (1803-1861). Zur Erinnerung an den hundertsten Todestag des Begründers der experimentellen Endokrinologie. Dtsch med Wschr 86:2186-2192

Skakkebaek NE, Bancroft J, Davidson DW, Warner P (1981) Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol 14:49-61

Snyder PJ, Lawrence DA (1980) Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 51:1335-1339

Sokol RZ, Swerdloff RS (1986) Practical considerations in the use of androgen therapy. In: Santen JR, Swerdloff RS (eds) Male reproductive dysfunction. Marcel Dekker, New York, pp 211-225

Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R; North American AA2500 T Gel Study Group (2003) AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 88:26732681

Stuenkel CA, Dudley RE, Yen SC (1991) Sublingual administration of testosterone hydroxypropyl-ß-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men. J Clin Endocrinol Metab 72:1054-1059 Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Longstreth J, Berman N (2000) Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab 85:4500-4510 van der Vies J (1965) On the mechanism of action of nandrolone phenylpropionate and nan-

drolone decanoate in rats. Acta endocrinol 49:271-282 van der Vies J (1970) Model studies in vitro with long-acting hormonal preparations. Acta endocrinol 64:656-669

van der Vies J (1985) Implications of basic pharmacology in the therapy with esters of nandrolone. In: Eikelboom FA, van der Vies J (eds) Anabolics in the '80s. Acta endocrinol, suppl 271, 110:38-44

Vest SA, Howard JE (1939) Clinical experiments with androgens. IV: a method of implantation of crystalline testosterone. J Am Med Assoc 113:1869-1872 Vogelzang NJ, Arnold JL, Chodak GJ, Schoenberg H (1986) Androgen and germ cell testicular cancers. JAMA 255:906-906 von Eckardstein S, Nieschlag E (2002) Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. J Androl 23:419-425 Voronoff S (1920) Testicular grafting from ape to man. Brentanos Ltd., London Wang C, Eyre R, Clark D, Kleinberg C, Newman I, Iranmanesh A, Veldhuis R, Dudley RE, Berman N, Davidson T, Barstow TS, Sinow R, Alexander G, Swerdloff R (1996) Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption and increases bone formation markers in hypogonadal men - a clinical research center study. J Clin Endocrinol Metab 81:3654-3662

Wang C, Berman N, Longstreth JA, Chuapoco B, Hull L, Steiner B, Faulkner S, Dudley RE, Swerdloff RS (2000) Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a general clinical research center study. J Clin Endocrinol Metab 85:964-969 Wang L, Shi DC, Lu SY, Fang RY (1991) The therapeutic effect of domestically produced testosterone undecanoate in Klinefelter syndrome. New Drugs Mark 8: 28-32 Weinbauer GF, Marshall GR, Nieschlag E (1986) New injectable testosterone ester maintains serum testosterone of castrated monkeys in the normal range for four months. Acta Endocrinol 113:128-132

Weinbauer GF, Partsch CJ, Zitzmann M, Schlatt S, Nieschlag E (2003) Pharmacokinetics and degree of aromatization rather than total dose of different preparations determine the effects of testosterone: a nonhuman primate study in Macaca fascicularis. J Androl 24:765-774

Werner SC, Hamger FM, Kritzler RA (1950) Jaundice during methyltestosterone therapy. Am J Med 8:325-331

Westaby D, Ogle SJ, Paradinas FJ, Randell JB, Murray-Lyon IM (1977) Liver damage from long-

term methyltestosterone. Lancet ii:261-263 World Health Organization, Nieschlag E, Wang C, Handelsman DJ, Swerdloff RS, Wu F, Einer-

Jensen N, Waites G (1992) Guidelines for the use of androgens. WHO, Geneva Wu FCW, Farley TMM, Peregoudov A, Waites GMH, WHO (1996) Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. Fertil Steril 65:626-636

Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ (1998) A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men. J Androl 19:761-768 Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E (2003) Prostate volume and growth in testosterone-substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a longitudinal pharmacogenetic study. J Clin Endocrinol Metab 88:2049-2054

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment