The ideal tissueselective androgen

The definition of "ideal" depends strongly on the clinical situation. The treatment of male hypogonadism has to reveal agonistic activities in muscle, bone and brain and no activity in e.g. the prostate. As indicated the dissociation of an androgen is implemented in vitro by recruitment of comodulators from which are known, they are expressed in the desired target tissues. For example FHL2 may coactivate androgen mediated action in the heart specifically and may be useful for heart muscle specific androgen benefits. In addition, recruitment of corepressors to the AR in prostate cells is beneficial to inhibit the androgen-dependent transactivation of target genes. For reasons to avoid undesired side effects, also androgens which are not 5a-reducible and therefore have no increased activity in organs with 5a-reductase (e.g. prostate, skin and hair follicle) are preferably used (see 20.2.1). Some beneficial androgen action especially in bone, brain and cardiovascular are not mediated by the androgen itself, but the aromatised product (see 20.2.1). The ideal tissue-selective androgen for hormone replacement should have the liability for aromatisation.

In male hypogonadism the internal testosterone secretion is already declined. A further decrease in testosterone production is not desired. Testosterone synthesis is positively controlled by gonadotrophins, especially LH. For that reason an ideal tissue-selective androgen for treatment of hypogonadism should not decrease LH secretion.

In comparison to hypogondism, the definition for an ideal dissociation is different in male contraception or PCa. For male contraception a reduction in gonadotrophins is necessary, for PCa protection it is desired. For PCa, an ideal dissociated androgen should have antagonistic action on the prostate, but maintaining agonistic effects on brain, muscle and bone, to avoid side effects, like hot flushes, loss of libido, mood disturbance, muscle wasting and osteopenia.

The requirements for female androgen substitution differ from males. Anabolic action on muscle and bone as well as libido are the positive effects of androgen action in women. Hirsutism, acne, male pattern baldness and voice change are severe side effects. In general a weak, but safe androgen is required, in order to avoid these side effects. Again an androgen which is not 5 a-reducible would be useful, as 5 a-reductase mainly enhances androgen action in skin and hair follicles (see 20.2.1). Alternatively, a SARM with antagonistic effects in these organs, but agonistic response in muscle, bone and brain would be ideal.

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