A hypothetical model of androgen action

Testosterone levels within the normal range will more or less saturate present androgen receptors and it has been demonstrated that androgenic effects will reach a plateau at certain levels, which are probably tissue-specific (Zitzmann etal. 2002a; 2002b). In agreement, a study applying exponentially increasing doses of testosterone to hypogonadal men shows corresponding results (Bhasin et al. 2001): androgen effects on various parameters increased linearly with the logarithm of testosterone levels and linearly with the logarithm of the testosterone dose. In practice, this means more or less a plateau effect. Significant increments of androgenic effects caused by rising testosterone levels within the eugonadal range are only seen beyond the normal range and when clearly supraphysiological levels are reached. Therefore, it can be assumed that within the range of such a plateau of saturation, genetically determined functional differences in androgen receptor activity can be best observed, while in a condition of hypogonadism, androgenicity will be strongly dependent on androgen levels as testosterone binds to androgen receptors and will increase androgen effects until saturation is reached (Figure 3.4). This model explains why androgen effects are found when comparing hypo- and eugonadal men, but can often not be confirmed for various testosterone levels within the eugonadal range. Indeed, the clinical distinction between hypo- and eugonadism

Eugonadism

Fig. 3.4 Hypothetical model of androgen effects: Within the hypogonadal range and in comparison to the eugonadal range, differences in androgen effects are determined by testosterone levels. Within the eugonadal range, androgen effects depend rather on the AR polymorphism. As this effect depends on the presence of AR co-activators, the concentrations of which are tissue-specific, the shapes of the curves are putatively variable from organ to organ.

Testosterone levels

Fig. 3.4 Hypothetical model of androgen effects: Within the hypogonadal range and in comparison to the eugonadal range, differences in androgen effects are determined by testosterone levels. Within the eugonadal range, androgen effects depend rather on the AR polymorphism. As this effect depends on the presence of AR co-activators, the concentrations of which are tissue-specific, the shapes of the curves are putatively variable from organ to organ.

is only possible when androgen effects do not increase in a linear fashion with testosterone levels. During substitution therapy of hypogonadal men, both effects on androgenicity, increment of testosterone levels from the hypo- into the eugonadal range and modulation of androgen effects within the eugonadal range by the androgen receptor polymorphism have to be taken into account.

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