fig1

Figure 1. The production of androgens is regulated by the hypothalamic-pituitary-gonadal-adrenal axes. AR activation (dimerisation and phosphorylation) is regulated by both androgen-dependent (blue arrows) and androgen-independent pathways (red arrows). In the androgen-dependent pathway, T and DHT production is catalysed by the steroidogenic enzymes and occurs through the canonical, 5a-dione and backdoor pathways^[24]. The androgen-independent pathway includes: (1) AR gain-function mutations; (2) activation by non-androgen steroids or androgen antagonists; (3) activation by non-steroid growth factors (receptor tyrosine kinases are activated and both AKT and MAPK pathways, producing a ligand-independent AR); and (4) increase of AR co-regulators. A parallel survival pathway, involving the anti-apoptotic protein BCL-2, also induces the cancer cell proliferation via bypassing the AR^[183,184]. AR: androgen receptor; GnRH: gonadotropin-releasing hormone analogues; T: testosterone; DHT: dihydrotestosterone; ARE: androgen response element; DHEA: dehydroepiandrosterone; LH: luteinizing hormone; ACTH: adreno-cortico-tropic-hormone