Endocrine Abstracts

Sex differentiation is the development of the internal and external genitalia following gonad determination. Genital ridge formation is regulated by WT1, SF1 and LHX9 whereas SRY is a major player in testis determination. Quite how SRY functions as a transcription factor is still unknown twelve years after the (i)SRY(/i) gene was cloned. How testis determination is regulated is incomplete, as the cause of sex reversal is unknown in the majority of patients with XY gonadal dysgenesis.

More is known about sex differentiation, essentially an androgenic process. Ligand-activation of the androgen receptor (AR) transcription factor regulates androgen-responsive genes expressed in the Wolffian ducts (vas deferens, epididymis, seminal vesicles) and the genital tubercle and folds (penis and scrotum). Studying the sex reversal syndromes, complete and partial androgen insensitivity, provides information on key components of transcriptional regulation. Mutant receptors may be enhanced in vitro by high androgen concentrations, an observation possibly of relevance clinically. The AR uniquely has motifs for interaction between the N- and C-terminal domains for optimal function.

Nuclear receptors also associate with co-regulators for efficient transcription regulation; more than 50 AR co-regulators are reported, with most also interacting with other receptors. A polymorphic glutamine region in the AR when hyper expanded causes spinobulbar muscular atrophy. Variations within the population range for CAG repeats are associated with prostate cancer, oligospermia, polycystic ovarian syndrome and hypospadias. The AR is a transcription factor which is androgen-activated and mediates a myriad of biological effects of androgens in target tissues. Most of the genes activated during these events remain to be identified.