Background: The androgen receptor (AR) is essential for the development of primary and secondary male characteristics and is activated by its ligand dihydrotestosterone (DHT). Reduced AR activity can cause undervirilization and infertility. We recently developed an assay to test AR function as a ligand-dependent transcriptional activator in human genital skin fibroblasts (GF). So far it is unclear, if AR expression levels correlate with AR function in the male external genitalia.
Objective and hypotheses: To analyse, if AR expression could be a surrogate for AR function in GF by correlating AR-expression levels with AR activity in GF from fertile adult males as well as children who have undergone orchidopexy.
Method: Cultured GF were derived from scrotal biopsies taken during vasectomy from fertile males as well as from boys during orchidopexy. In these GF AR mRNA expression was analyzed and, in parallel, AR transcriptional activity was determined through DHT-dependent induction of the androgen regulated AR target gene apolipoprotein D (APOD). A correlation coefficient was calculated between APOD induction (AR activity) and AR expression.
Results: Vasectomy patients (fertile males n=29) showed a three- to fivefold APOD induction upon DHT treatment. AR expression varied widely leading to a low correlation coefficient between AR expression and AR activity (0.12). In contrast, boys who had undergone orchidopexy (n=10) showed a wider range of APOD induction which correlated highly with AR expression (0.84). AR expression levels did not differ significantly between adults and children and did not correlate with age.
Conclusion: Our data show that during childhood, AR activity is closely linked to AR mRNA expression levels while this interrelation gets lost in adulthood. This suggests a profound biological change in the mechanism of regulation of cellular androgen sensitivity in different developmental stages from childhood to adulthood in the male. Biologically, this difference may be linked to the existing growth potential of the external genitalia in boys in response to pubertal androgen while genital outgrowth comes to a fixed end in adult males despite the long-term presence of high androgen.
Funding: German Research Council (DFG; HO2073/7-1 and AM343/2-1).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology