Introduction

Male reproductive function is influenced by non-gonadal disease so that mild androgen deficiency is a regular feature of chronic disease, which, if sufficiently severe or prolonged may contribute to the pathophysiology. Additionally, andro-gens are potent therapeutic drugs with effects on androgen-sensitive tissues such as muscle, bone, brain, liver or adipose tissue that maybe exploited for therapeutic benefit.

As an adjunct to standard medical care, androgen therapy maybe considered as either physiological androgen replacement or pharmacological androgen therapy. Androgen replacement therapy aims to replicate endogenous androgen exposure thereby limiting it to the use of testosterone in doses intended to produce physiological blood concentrations. To the degree it replicates endogenous androgen exposure, the expectation for safety may reasonably be compared with the benchmark of life-long health experience of eugonadal men. By contrast, pharmacological androgen therapy is no different from pharmacotherapy with any xenobiotic drug used to achieve a therapeutic goal. It utilises an androgen, without restriction to testosterone or reference to replacement doses, to optimal effect as judged by the standards of efficacy, safety and cost-effectiveness applicable to other drugs. Pharmacological androgen therapy has often involved synthetic oral androgens rather than testosterone, usually the hepatotoxic 17a-alkylated androgens now considered obsolete for androgen replacement therapy. While occasionally justified by the need to avoid parenteral injections due to bleeding disorders or for deliberate hepatic targeting via oral first pass effects, this involves an avoidable risk of hepatotoxicity.

Development of selective designer androgens in the future should open new possibilities for further investigation of adjuvant pharmacological androgen therapy. These designer androgens would be based on tissue-specific activation to aromatised and/or 5a-reduced metabolites or on co-regulator distribution patterns, rather than being "anabolic steroids", an outmoded term referring to non-virilising androgens targeted exclusively to muscle, a concept lacking biological proof of principle.

The goals of androgen therapy for non-gonadal disease must be considered in relation to the natural history of the underlying disease. Mild androgen deficiency is a frequent biochemical accompaniment of systemic disease. If unusually severe or prolonged, androgen deficiency may contribute to morbidity from the underlying disease. Physiological androgen replacement therapy in itself is unlikely to influence mortality, as complete androgen deficiency due to congenital androgen resistance or castration before or after puberty does not appear to reduce life expectancy (Liu et al. 2003a; Nieschlag et al. 1993). Hence most studies of pharmacological androgen therapy in systemic disease aim ideally to modify the natural history of the underlying disease but otherwise to palliate symptoms and improve quality of life. The natural history of the underlying disease must also be considered to evaluate the relative importance of potential long-term hazards (such as acceleration of prostate or cardiovascular disease) compared with possible immediate benefits that pharmacological androgen therapy might achieve for quality of life.

This chapter focuses on controlled clinical studies reported over the last few decades rather than the plethora of studies performed over the six decades since testosterone was first used clinically (Foss 1939; Hamilton 1937). A comprehensive account of early, mostly uncontrolled studies of androgen therapy up to the mid-1970s is contained in two classical textbooks (Kopera 1976; Kruskemper 1968). Recognising there are few if any well-established indications for pharmacological androgen therapy, placebo controls remain the conditio sine qua non for high-quality clinical studies. In addition, other optimal trial design features include adequate power and duration with valid, objective end-points. Unfortunately, few studies fulfil these stringent requirements, most comprising observational and/or mechanistic studies, which provide little reliable guidance for practical therapeutics. Observational studies of systemic disease effects on male reproductive health are reviewed elsewhere (Handelsman 2001).

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