Metabolism of androgens in different tissues

In adult men testosterone itself is the hormone governing libido, gonadotropin feedback regulation, and growth and function of extragenital tissues, such as muscle, kidney, liver, and bone. When testosterone diffuses from the outside into the cytosol of cells, it binds either to AR directly, or is converted into DHT with higher affinity to the receptor, or, after it is aromatised to estradiol (E2) it can interact with ERa or ERp. In addition, it is feasible that the androgen is metabolised to an inactive compound which has no effect on NR target genes or on cellular function.

Testosterone is metabolised to the more active androgen dihydrotestosterone (DHT) by 5a-reductase, which has much greater affinity to the AR than T and enhances AR-mediated transcription of target genes amplifying therefore the action of testosterone. The reductase is expressed especially in organs like skin, hair follicle and prostate and thereby contribute to undesired side-effects of androgens on baldness, acne, hirsutism (in women) and on the prostate.

Testosterone is also metabolised in vivo to E2 by aromatase which is in male predominantly expressed in brain, liver and adipose tissues exerting estrogenic activity and leading to the activation of estrogen-responsive target genes (Harada etal. 1993; McEwen 1980; Nimrod and Ryan 1975; Simpson etal. 1994). Therefore, the androgens have the potential to activate a different set of target genes after tissue-specific aromatisation to estrogens. Indeed several beneficial effects on the brain, as well as bone protection, libido and reproduction, are most likely mediated not by the androgen itself, but by its aromatised product. The additional effects of aromatization were described for the preservation of osteopenia (for overview Riggs et al. 2002) and neuroprotection (Azcoitia et al. 2001). A similar role for estrogens in enhancement of libido in human is controversially discussed in the literature (e.g. Gooren 1985; Roselli and Resko 2001). Most data clearly supporting the hypothesis were from studies in birds or rats. However, the few data available from human and other primates stressed the importance of not only systemical estrogens (Carani et al. 1999), but also locally synthesised estrogens (Zumpe et al. 1993).

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