12 Features April 2009 © 2009 The Biochemical Society Sex hormones The effect of androgen receptors on male fertility What makes a Androgens are the major drivers of masculinization and male fertility, and disruption of androgen signalling has been implicated in the most common male congenital abnormalities, such as hypo‑ spadias (opening of the urethra in a position not at the tip of the penis) and cryptorchidism (testes in the abdomen not the scrotum), as well as with an increased risk of developing testicular cancer or having a low sperm count in adulthood 1 . domain (DBD), a hinge region and a ligand-binding domain (LBD) (Figure 1). In comparison with the other domains, the N-terminal domain apparently lacks a stable structure, but does contain target sites for phosphorylation as well as polyglutamine and polyglycine repeats; the length of the repeat sequenc- es can alter AR function 3 . AR functions primarily as a transcription factor. In the absence of ligand, AR is predominantly local- ized to the cytoplasmic compartment, where it exists in an inactive complex with components including heat-shock proteins. Upon ligand binding, AR binds as a homodimer to DNA at specific target sequences termed androgen-response elements (AREs) located in the promoters of target genes (Figure 2). Studies using ARs lacking the LBD have shown that both this part of the receptor, as well as the DBD, are essential for stable binding of AR to DNA. The transcriptional activity of AR is regulated not only by ligand bind- ing but also by interactions between the N- and C-terminal domains of the protein and interactions The two most important androgens in the male are testosterone, which is produced by the Leydig cells (LCs) of the testis, and dihydrotestosterone (DHT), which is generated from testosterone by the enzyme 5α-reductase in androgen target tissues including the prostate. Results obtained in studies treating a vari- ety of animals with exogenous androgens have gone some way towards elucidating the general roles these hormones play in development and fertility. However, there is an increasing appreciation that local metabo- lism of testosterone and/or DHT may also contribute to changes observed in reproductive function. For ex- ample, testosterone can be converted into the ‘female’ hormone oestradiol by the enzyme aromatase that is present in both the testes and other parts of the male reproductive system. Oestrogens work by activating the oestrogen receptors (ERα, ERβ); as both of these are found in the testis and other male organs, there is clearly an opportunity for alternative pathways of gene activation reproductive system 2 . Thus, in or- der to elucidate the specific functions of androgens in development and fertility, independent of the ef- fects of other steroid hormones, renewed energy has been directed towards perturbation of the signalling cascade at the level of the androgen receptor (AR), rather than the androgens themselves. The androgen receptor The AR is a member of the superfamily of steroid hormone receptors, and is encoded by a single gene located on the X-chromosome that produces a pro- tein of ~920 residues (~110 kDa). The protein struc- ture of AR consists of four functional domains, an N-terminal transactivation domain, a DNA-binding Lee B. Smith and Philippa T.K. Saunders (MRC Human Reproductive Sciences Unit, Edinburgh) Figure 1. Diagram of the human AR protein showing the loca‑ tions of the diferent domains. Orange indicates the NTB/A/B, N‑terminal domain; purple indicates the DBD/C, DNA‑binding domain; red indicates D, hinge domain; green indicates LBD/E, ligand‑binding domain: yellow indicates F domain. The NTB contains two regions of with variable numbers of glutamine (Q) and glycine (G) residues; three activation function domains (AF1, AF5, AF2) containing residues that can be phosphory‑ lated have also been identifed Key words: androgen, dihydrotestosterone, male fertility, spermatogenesis, steroid hormone receptor, testosterone Downloaded from http://portlandpress.com/biochemist/article-pdf/31/2/12/4964/bio031020012.pdf by guest on 26 February 2023