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    • Testosterone can be converted into estrogens by

    2023-08-14

    Testosterone can be converted into estrogens by aromatase action. Aromatase is encoded by CYP19, belongs to cytochrome P450 superfamily, and synthesizes estradiol (E2) and estrone (E1) from testosterone and androstenedione respectively (Fig. 1). Aromatase is expressed in the ORS of anagen hair follicle and in the sebaceous glands, but not in telogen hair follicles. Although, the expression was not uneven among body sites and gender, aromatase activity in women with AGA showed to be 2-fold higher in occipital compared to frontal hair follicles, and 6 to 3-fold higher in frontal and occipital sites, respectively, compared to men with AGA. Frontal follicles of women had almost twice aromatase activity than frontal hair follicles of men with AGA (Sawaya and Price, 1997, Sawaya and Penneys, 1992). Therefore aromatase activity in the skin can serve to fine tune the regulation of androgens and estrogens levels in target Oligomycin Complex (Ohnemus et al., 2006). Given that DHT cannot be deviated to other non-androgenic pathways, it keeps its androgenic action unless it is degraded by another enzyme. This regulatory action is performed by 3α-HSD that catalyzes conversion of 5α-DHT into 3α-adiol (Fig. 1). This enzyme is mainly expressed in liver and regulates steroid hormone levels.
    Androgen receptor in skin The action of androgens such as testosterone and DHT on skin is mainly mediated via the androgen receptor (AR), a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor superfamily (Chang et al., 1995). Therefore, the lack of a functional AR results in severe alterations in the normal physiology of skin specially associated to the development and physiology of skin appendages (Zouboulis and Degitz, 2004). The AR gene is located on the X chromosome as a single copy so that males are hemizygous, and inactivating mutations result in the testicular feminization syndrome (Quigley et al., 1995). The N-terminal domain is the most variable, whilst the DBD is the most highly conserved region among the different members of the steroid hormone nuclear receptor family. Given the scarce variability between the DBDs, binding to selective androgen response elements (AREs) allows for the specific regulation of AR target genes (Heinlein and Chang, 2002). The DBD is linked to the conserved ligand-binding domain by a hinge region. The ligand-binding domain allows physical association between the AR and heat shock proteins (HSP) in basal state. It also interacts with the N-terminus of the AR to stabilize bound androgens. Moreover, AR sequence includes: two transcriptional activating functions AF-1 and AF-2 (Wilson, 2011, Callewaert et al., 2006), a nuclear localization signal (NLS) and a nuclear export signal (NES) (Tan et al., 2015). When AR interacts with its androgen ligand, it dissociates from HSPs, and the receptor-ligand complex translocates to the nucleus and binds to AREs in the promoter region of androgen-regulated genes inducing their transcription in a DNA binding-dependent manner. On the other hand, androgens can exert their actions via the AR in a non-DNA binding-dependent manner, by initiating a rapid activation of second messenger signaling cascades. Moreover, ligand-independent actions of the AR have been identified recently (Reviewed in (Davey and Grossmann, 2016)). Various coregulators can modulate AR function through their binding to the ligand-binding domain or the N-terminal domain, and there are more than 200 AR coregulators identified including transcriptional factors, kinases, chaperones, cytoskeletal proteins, among others (van de Wijngaart et al., 2012). AR is ubiquitously expressed in the body and displays diverse functions, either stimulating or inhibiting cell growth, in different target organs or tissues. Localization of AR was widely studied in the human skin and its appendages. AR is expressed in epidermal keratinocytes, dermal fibroblasts and vascular endothelial cells in both neonatal foreskin and skin from adult men and women (Liang et al., 1993). In eccrine sweat glands, only few secretory cells were observed to express AR however in the sebaceous glands AR is detected in both basal cells and sebocytes.