General considerations

Although testosterone has been in clinical use for almost 70 years, it has only slowly attracted interest from clinical researchers. This is partly due to the fact that hypogondal men requiring testosterone treatment constitute only a minority of all patients and hypogonadism is not a life-threatening disease. Since development of new preparations is mainly a task of the pharmaceutical industry and hypogonadal patients did not promise to contribute a substantial economic profit, development of testosterone preparations was slow. Only recently has the question of testosterone treatment of senescent men (see Chapter 16) and, to a certain extent also the search for a hormonal male contraceptive (see Chapter 23) spurred interest in the pharmacology and application of testosterone.

To day oral, buccal, injectable, implantable and transdermal testosterone preparations are available for clinical use. There are only a few studies available comparing the various preparations with the goal of identifying the optimal preparation for substitution purposes (Conway et al. 1988). While the older injectable preparations, which are still the predominant form for substitution, produce sup-raphysiological serum testosterone levels, newer preparations achieve levels closer to the physiological range. We are only beginning to understand which serum levels are required to achieve the various biological effects of testosterone and to avoid adverse side-effects. In particular, very little is known about long-term effects of testosterone therapy inherent to different preparations. Similarly, the role of the androgen receptor polymorphism in modifying testosterone action individually is becoming understood only slowly, but may lead to a pharmacogenetic concept for the therapeutic application of testosterone (e.g. Zitzmann et al. 2003). Under these circumstances it appears that the consensus reached by a Workshop Conference on Androgen Therapy organised jointly by WHO, NIH and FDA in 1990 still provides the best therapeutic guidelines: "The consensus view was that the major goal of therapy is to replace testosterone levels at as close to physiologic concentrations as is possible" (WHO 1992). Until other evidence is provided, all testosterone preparations will best be judged by this principle.

An important question is which androgen preparation should be used for clinical purposes. Numerous androgenic steroids have been synthesized and used clinically in the past. The synthetic androgens were produced with the aim to enhance selectively certain aspects of testosterone activity e.g. the anabolic effect on muscles or the hematopoietic effect. Some of these molecules proved to have toxic side-effects, in particular upon long-term use (as required for substitution of hypogonadism) or the desired efficacy and safety were inadequate in controlled clinical trials (as advocated by evidence-based medicine). In addition, some of these steroids cannot be converted to 5a-DHT or estrogen, as is testosterone, and therefore cannot develop the full spectrum of activities of testosterone. The important biological significance of these conversions is described in Chapters 1 to 3 of this volume. For these reasons, synthetic preparations have almost disappeared from the market and testosterone as produced naturally is the prevailing androgen used in clinical medicine. In its various preparations testosterone has been available for over six decades and, as one of the oldest "drugs" in clinical use, has demonstrated its high safety.

Fig. 14.1 Molecular structure of testosterone and clinically used testosterone esters and derivatives.

However, new insights into the molecular mechanisms of androgen action may lead to the development of steroids suited for specific purposes (see Chapter 20). 7a-methyl-19-nortestosterone serves as an example, as it is experiencing a renaissance due to its high androgenicity combined with low prostatotropic effects shown in hypogonadal patients (Anderson etal. 2003). Whether such steroids may become useful and safe for clinical use remains to be seen.

This chapter provides an overview of the various conventional and new testosterone preparations used in clinical medicine.

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