Comparing the rules of engagement of androgen and glucocorticoid receptors

Abstract

Despite the diverse physiological activities of androgens and glucocorticoids, the corresponding receptors are very close members of the nuclear-receptor super family. Their action mechanisms show striking similarities, since both receptors recognize very similar DNA-response elements and recruit the same coactivators to their target genes. The specificity of the responses lies mainly in the tissue-specific expression of the receptors and in their ligand specificity. In cells, where both receptors are expressed, the mechanisms leading to the difference in target genes are less obvious. They lie in part in subtle variations of the DNA-binding sites, in cooperativity with other transcription factors and in differential allosteric signals from the DNA and ligand to other receptor domains. We will highlight the different suggestions that might explain the DNA sequence selectivity and will compare the possible allosteric routes between the response elements and the different functions in the transactivation process. The interplay of androgen and glucocorticoid receptors is also highly relevant in clinical settings, where both receptors are therapeutically targeted. We will discuss the possibility that the glucocorticoid and androgen receptors can play partially redundant roles in castration-resistant prostate cancer.

Altered stress hormone response following acute exercise during prostate cancer treatment

“…We are not aware of any evidence directly showing that these medications influence circulating cortisol. However, numerous similarities between androgens and glucocorticoids and their respective receptors suggest that some forms of ADT influence the cortisol response …”

“…While the stress hormone response to exercise is unclear in patients with PCa, there is evidence of interactions between the hypothalamic‐pituitary‐adrenal (HPA) and hypothalamic‐pituitary‐gonadal (HPG) axes in other populations, with chronic activation of the stress systems leading to decreased production of sex and growth hormones . Excess glucocorticoid production due to chronic stress leads to loss of lean mass and increases in visceral adiposity and insulin resistance, potentially exacerbating these symptoms already associated with ADT.…”

Testosterone, Cortisol and Financial Risk-Taking

“…Though both testosterone and cortisol have powerful influences on decision-making, there are important differences as well as similarities between the hormones themselves. Both are steroids, which means that the cellular action they have on neurons is similar to the extent that both act on intracellular steroid-binding molecules, receptors, which are reasonably but not entirely specific for each hormone (Claessens et al, 2017 ; Gray et al, 2017 ; Maney, 2017 ). There is also evidence for a second, more rapidly acting membrane-bound receptor for both steroids (Vernocchi et al, 2013 ; Shihan et al, 2014 ).…”

Rationale for the development of alternative forms of androgen deprivation therapy

“…Initially, studies focused on distinguishing between the mechanisms by which AR and related nuclear receptors, such as the glucocorticoid receptor (GR), which are recruited to highly similar DNA motifs using structurally similar protein domains, bind selectively to their respective cognate genomic binding site. Although still far from understood completely, the current consensus is that AR binds as a dimer in a head-to-head conformation to inverted repeats of a 5′-AGAACA-3′ hexamer that are separated by 3 bases (Claessens, et al 2017). We will refer to this 15-mer sequence as the canonical ARE motif.…”