Androgens are C19 steroids that are male sex hormones responsible for differentiation and maintenance of the male genitalia and libido, spermatogenesis, and the development of secondary male characteristics. Androgens also have anabolic effects on the skeletal muscle and maintain bone. In the adult male, testosterone (T) is the major circulating hormone produced in the Leydig cells of the testis in response to luteinizing hormone (LH). A more potent hormone is made in peripheral tissues, namely 5α-dihydrotestosterone (DHT) and is produced by steroid 5α-reductase type 1 (SRD5A1), type 2 (SRD5A2) (Russell & Wilson, 1994) and type 3 (SRD5A3) (Uemura et al., 2008), Fig. 1. Although SRD5A3 catalyzes the conversion of T to DHT and shows elevated expression as prostate cancer progresses (Titus et al., 2014), it is also known as polyprenol reductase which is essential for dolichol formation (Cantagrel et al., 2010).

Changes in serum androgens occur throughout the lifespan. In the neonate there is surge of androgen production to complete the differentiation of the male genitalia (to prevent hypospadias) and is required for the descent of the testis (to prevent cryptorchidism). This is followed by a quiescent period until puberty, and as men age there is a decrease in androgen levels leading to a loss of libido, skeletal muscle mass and bone (often referred to as andropause).

T and DHT mediate their effects by binding to the androgen receptor (AR). These ligands have differential effects that were identified by SRD5A2 deficiency (Peterson, Imperato-McGinley, Gautier, & Sturla, 1977). This deficiency is characterized by pseudo-hermaphroditism, an atrophied prostate, and lack of facial hair. SRD5A2 deficiency is accompanied by the appearance of a penis at puberty showing that there are differential effects of T and DHT on male development. By contrast genetic deficiency in SRD5A3 is primarily associated with a congenital glycosylation disorder consistent with its role in dolichol biosynthesis (Cantagrel et al., 2010). SRD5A3 deficiency does not recapitulate pseudo-hermaphroditism reminiscent of SRD5A2 deficiency and the inability to synthesize DHT. The ability of T and DHT to have differential effects on male development raises one apparent paradox in AR signaling, which is why is it that two hormones that bind to the same receptor have these different effects? (see Section 6.5).

The gene for the AR is located on the X-chromosome at locus Xq11-Xq12 and cDNAs for portions of the human AR were reported by three groups almost simultaneously (Chang, Kokontis and Liao, 1988a, Chang, Kokontis and Liao, 1988b; Lubahn et al., 1988; Trapman et al., 1988). This was later followed by the complete sequence of the AR cDNA and its functional expression in COS-1 cells using ligand binding assays (Tilley, Marcelli, Wilson, & McPhaul, 1989). The cDNA revealed a full-length AR (AR-FL) of 919 amino acids, that consisted of four domains in common with other NRs. Based on the NR superfamily nomenclature, the AR is formally NR3C4, Fig. 2 (Evans, 1988).

The AR domain structure consists of an intrinsically disordered N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region which contains a nuclear localization signal (NLS), and a C-terminal ligand-binding domain (LBD). The cysteine-rich DNA-binding domain (amino acids 557–662) showed 85%, 79%, and 80% conservation with the amino acids in DBD of the progesterone receptor (PR), the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), respectively. The LBD had 54%, 50% and 51% amino acid identity with the LBD of the PR, GR, and MR, respectively Fig. 3. The largest differences in sequence identity and domain length occur in the NTD. Despite these advances in cDNA cloning, sequence alignment and domain organization, a high-resolution structure of the AR-FL has remained elusive.

The AR acts as a ligand activated transcription factor and in unbound form is located in the cytosol of target tissues where it is stabilized by heat shock proteins (hsp90, hsp70 and hsp40). Upon binding ligand this protein–protein interaction is disrupted, the NLS is exposed and the liganded AR is translocated to the nucleus via importin-α (Cutress, Whitaker, Mills, Stewart, & Neal, 2008). In the nucleus, liganded AR binds to androgen response elements (AREs) on exposed chromatin. The AREs are identical to the response elements for PR, GR, and MR. This model of AR signal transduction presents questions and paradoxes. At what point does the AR dimerize? If the AREs are identical with those for PR, GR and MR how can the hormone response be specific? This rudimentary model of AR signaling also does not explain the structural basis of agonism and antagonism, or the basis by which selective androgen receptor modulators (SARMs), which are designed to separate androgenic and anabolic effects mediate their effects. Nor does the model explain how AR action is terminated after ligand mediated transcription has occurred. This review will describe recent advances in AR structure, AR signaling, AR-SVs, and AR-pharmacology that offer some insight to these paradoxes and questions.