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Androgen Replacement Therapy Present and Future

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Androgen Replacement Therapy Present and Future Drugs 2004; 64 (17): 1861-1891 REVIEW ARTICLE 0012-6667/04/0017-1861/$34.00/0 2004 Adis Data Information BV. All rights reserved. Androgen Replacement Therapy Present and Future Louis J.G. Gooren and Mathijs C.M. Bunck Department of Endocrinology, Section of Andrology, VU University Medical Center, Amsterdam, The Netherlands Contents Abstract...................................................................................1862 1. Androgen Replacement Therapy: General Considerations .................................1862 1.1 Testosterone ......................................................................1862 1.2 Estrogens .........................................................................1864 1.3 Nongenomic Actions of Androgens and Estrogens ....................................1865 1.4 Transport of Androgens ............................................................1865 1.5 Quantitative Aspects of Androgen Action ...........................................1865 1.6 Plasma Testosterone Levels Required for Androgen-Related Biological Functions .........1865 2. Available Preparations for Testosterone Replacement .....................................1866 3. Oral and Sublingual Administration ......................................................1866 3.1 Transdermal Delivery ...............................................................1869 3.1.1 Scrotal Testosterone Patch ....................................................1869 3.1.2 Nonscrotal Testosterone Patch ................................................1870 3.1.3 Testosterone Gel .............................................................1870 3.2 Intramuscular Administration ........................................................1871 3.2.1 Testosterone Esters ...........................................................1871 3.2.2 Testosterone Bucyclate .......................................................1872 3.2.3 Testosterone Microspheres ....................................................1872 3.2.4 Testosterone Undecanoate ...................................................1872 3.3 Testosterone Implants ..............................................................1872 3.4 Androgen Replacement with 5α-Reduced Testosterone: 5α-Dihydrotestosterone ........1874 4. Adequacy of Androgen Replacement: Biochemical and Clinical Endpoints .................1875 4.1 Recent Insights into Androgen Action ................................................1876 5. Towards Novel Androgen Preparations ...................................................1876 6. A Selective Androgen: 7α-Methyl-19-Nortestosterone ......................................1877 7. Target Organs of Androgens ............................................................1878 7.1 Muscles ...........................................................................1878 7.2 Bones ............................................................................1878 7.3 Skin ..............................................................................1879 7.4 Androgens and Sexual Functioning ..................................................1879 7.5 Androgens and Cognitive Performance .............................................1879 7.6 Estrogenic Actions of Androgens ....................................................1880 8. Modifications to Limit Potentially Negative Effects of Androgens ............................1881 8.1 Cardiovascular Aspects ............................................................1881 8.2 Prostate ..........................................................................1881 8.2.1 Estrogens and Prostate Disease ...............................................1882 9. Requirements for the Various Androgen Treatment Indications .............................1883 9.1 Induction of Virilisation .............................................................1883 9.2 Maintenance of Virilisation .........................................................1884 9.3 Aging Males ......................................................................1884 9.4 Androgen Administration to Women .................................................1884 10. Conclusion ............................................................................1884 1862 Gooren & Bunck Abstract The major goal of androgen substitution is to replace testosterone at levels as close to physiological levels as is possible. For some androgen-dependent func- tions testosterone is a pro-hormone, peripherally converted to 5α-dihydrotestos- terone (DHT) and 17β-estradiol (E2), of which the levels preferably should be within normal physiological ranges. Furthermore, androgens should have a good safety profile without adverse effects on the prostate, serum lipids, liver or respiratory function, and they must be convenient to use and patient-friendly, with a relative independence from medical services. Natural testosterone is viewed as the best androgen for substitution in hypogonadal men. The reason behind the selection is that testosterone can be converted to DHT and E2, thus developing the full spectrum of testosterone activities in long-term substitution. The mainstays of testosterone substitution are parenteral testosterone esters (testosterone enantate and testosterone cipionate) administered every 2–3 weeks. A major disadvantage is the strongly fluctuating levels of plasma testosterone, which are not in the physiological range at least 50% of the time. Also, the generated plasma E2 is usually supraphysiological. A major improvement is parenteral testosterone undecanoate producing normal plasma levels of testoster- one for 12 weeks, with normal plasma levels of DHT and E2 also. Subcutaneous testosterone implants provide the patient, depending on the dose of implants, with normal plasma testosterone for 3–6 months. However, their use is not widespread. Oral testosterone undecanoate dissolved in castor oil bypasses the liver via its lymphatic absorption. At a dosage of 80mg twice daily, plasma testosterone levels are largely in the normal range, but plasma DHT tends to be elevated. For two decades transdermal testosterone preparations have been available and have an attractive pharmacokinetic profile. Scrotal testosterone patches generate supra- physiological plasma DHT levels, which is not the case with the nonscrotal testosterone patches. Transdermal testosterone gel produces fewer skin irritations than the patches and offers greater flexibility in dosage. Oromucosal testosterone preparations have recently become available. Testosterone replacement is usually of long duration and so patient compliance is of utmost importance. Therefore, the patient must be involved in the selection of type of testosterone preparation. Administration of testosterone to young individuals has almost no adverse effects. With increasing age the risk of adverse effects on the prostate, the cardiovascular system and erythropoiesis increases. Consequently, short-acting testosterone preparations are better suited for aging androgen-deficient men. 1. Androgen Replacement Therapy: ally irreversible. The consequence is that life-long General Considerations androgen replacement is required; however, patient compliance with life-long androgen replacement de- 1.1 Testosterone pends on convenient pharmaceutical formulations ensuring continuity of androgen replacement. The Androgen replacement therapy (ART) aims to traditional association is that androgens mainly sub- replace physiological actions of endogenous testos- serve male sexual functioning, but studies over the terone by steadily maintaining physiological blood last two decades have convincingly shown that the levels of testosterone.[1] The underlying conditions actions of androgens are much broader, including that render androgen replacement necessary are usu- those on bone, muscle, cardiovascular functions and 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (17) Androgen Replacement Therapy 1863 brain and, consequently, androgens have a profound terone is the biologically active androgen; in other impact on quality of life.[2,3] target organs the actions of testosterone depend on The benefits of ART are clear, but the delivery of its local enzymatic conversion to DHT and/or E2. testosterone to hypogonadal men in a way that ap- DHT is the most potent natural androgen, and it proximates normal levels and patterns still poses a is formed exclusively through 5α-reduction of tes- therapeutic challenge. Developing an ideal form of tosterone by the enzyme 5α-reductase. This enzyme ART requires much effort. Among experts, there is has two forms produced by distinct, homologous consensus that the major goal of testosterone substi- genes: type 1 5α-reductase expressed in liver, skin tution is “to replace testosterone levels at as close to and brain; type 2 5α-reductase which is characteris- physiological levels as is possible”.[1] General tically expressed strongly in the prostate and at agreements about such an ART are: (i) a delivery of lower levels in skin and liver.[5] The functional the physiological amount of testosterone (3–10 mg/ predominance of prostatic expression of type 2 5α- day); (ii) consistent levels of testosterone, 5α- reductase made it feasible to develop a prostate [6] dihydrotestosterone (DHT) and 17β-estradiol (E2) targeted 5α-reductase inhibitor, finasteride, with within normal physiological ranges; (iii) similar cir- the organ specificity. Recently, a new 5α-reductase cadian patterns of hormone levels as in healthy inhibitor, dutasteride, has been introduced. Dutas- young men;
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