br Conclusions br Declarations br Introduction The classical

Conclusions
Declarations
Introduction The classical term of endocrine disruption includes any agent that interferes with the action of hormones within the human body; these agents are therefore named endocrine disruptors. Among these agents, that are mainly environmental chemicals (pollutants), known to alter male reproduction and increase reproductive tract cancers (in the case of androgens), there is a significant number of plant derived compounds that can also interfere with their action. They have been characterized as antiandrogens, due to their ability to block or suppress testosterone action through several mechanisms, including the Harringtonine with androgen for their receptor binding sites. In this review we will present an up to date summary knowledge on how natural compounds can interfere with the classical androgen receptor mediated actions, along with their interaction with extranuclear and membrane initiated androgen effects. Additionally, we extent the notion of hormone disruption by presenting novel, surprising evidence that androgens as well as natural androgen-interacting ligands can interfere with other cell membrane receptor systems providing an alternative mode of extranuclear androgen action.
Natural agents and the androgen receptor In contrast to estrogen actions (with breast cancer being the prototype disease), through the estrogen receptor (ER) cluster, integrating ERα and β, ER variants and GPR30/GPER1, for which several molecules has been developed and introduced in clinical practice, androgen receptor competition and disruption has not received a similar attention. This might be due to the fact that prostate cancer, an androgen receptor (AR)-related disease, was found to express almost ubiquitely AR, and therefore this molecule is not routinely assayed in prostate cancer, neither as a diagnostic biomarker or companion therapeutic assay (Pelekanou and Castanas, 2016). Nevertheless, in recent years, an increased interest in AR detection and disruption of its action was expressed, as AR have been detected in a number of additional pathologies (including breast cancer), while a deeper insight of AR action has been found, together with alternative modes of action (Pelekanou et al., 2013, Pelekanou et al., 2007). The classical mode of action of androgens is mediated by their binding to a specific androgen receptor, that belongs to the nuclear receptor superfamily. AR is a 919 aminoacid protein that contains four distinct domains: the N-terminal domain, the DNA binding domain, a hinge region and the ligand binding domain (Claessens et al., 2008). All domains contain one signal for the nuclear transport of AR, while the N-terminal domain and the ligand binding domain have transcription activation functions that allows AR interaction with co-regulators (Dubbink et al., 2004, Kaku et al., 2008). AR is mainly found in the cytoplasm as a dimer and is complexed to heat shock proteins. When androgen binds to AR, the AR dimer is released, becomes phosphorylated and interacts with several co-regulators that promote its translocation to the nucleus, and its binding to DNA at specific sites, the so-called androgen response elements (AREs). As a consequence, the transcription of a number of genes is affected and a specific cellular androgenic response is initiated (Heemers and Tindall, 2007). Most plant-derived compounds exert an anti-androgenic action by lowering testosterone levels, either by preventing its conversion to the more potent DHT, by promoting its conversion to estrogens, or by reducing prolactin release and subsequent FSH and testosterone levels, these hormones being directly related to testosterone production-secretion by Sertoli cells. For example epigallocatechins from green tea (Camellia sinensis), a red reishi mushroom (Ganoderma lucidum) extract (mainly its triterpenoids containing fraction) inhibit the 5-alpha-reductase conversion of testosterone into DHT (Fujita et al., 2005, Liao and Hiipakka, 1995), while paeoniflorin, a compound found in white peony (Paeonia lactiflora), was found to inhibit the production of testosterone and increase aromatase activity promoting its conversion to estrogens (Takeuchi et al., 1991). Additionally, a chaste tree extract (Vitex agnus-cactus) reduces testosterone via dopaminergic effects that result in reduced prolactin from the anterior pituitary (Nasri et al., 2007, Webster et al., 2011) although this effect on testosterone is contradicted by others (Jarry et al., 1994). A decrease in testosterone levels has been also described by a Licorice extract (Glycyrrhiza glabra) that decreases total testosterone levels (Armanini et al., 1999) and for spearmint (Mentha spicata) that specifically reduces free testosterone (Akdogan et al., 2007), without any effect on total testosterone concentration.