Androgens and the masculinisation programming window

The commonest reproductive disorders of young men ( namely low sperm counts, testicular germ cell cancer) may originate in fetal life similar to established disorders (cryptorchidism, hypospadias) that manifest at birt h. These disorders are interlinked and may comprise a testicular dysgenesis syndrome (TDS) , a concept supported by animal model studies. The latter have identified the likel y time-frame within which TDS disorders may be induced, namely within the so-call ed masculinisation programming window (MPW). During this critical period, sufficie nt testosterone (androgen) must be produced by the fetal testis to program the male re productive tract so that it will differentiate and grow normally after the MPW. Impa ired androgen production or action within the MPW can result in smaller reproductive o rgans and their abnormal formation and function (e.g. cryptorchidism, hypospadias). The MPW is thus of fundamental importance in determ ining normal, or abnormal, male reproductive development and function for later lif e. There are two big unanswered questions about the MPW. First, what determines its timing? Second, what mechanisms are controlled by androgens specifically within thi s time-window and not at later time points? Three approaches were undertaken to address the first question experimentally in rats. First, investigation of whether the availabil ity of androgens and or androgen receptors (AR) plays a role in determining the onse t or ‘opening’ of the MPW. Second, investigation of whether the expression of AR co-re gulators was a factor in determining androgen sensitivity during the MPW. Third, investi ga on of whether prostaglandins played a role in mediating androgen action in the M PW, as studies in the 1980s had suggested this possibility. To address what mechani sms are controlled by androgens specifically within the MPW, the expression of sele cted genes in the genital tubercle was investigated before, during and after the MPW in fe tus s that had been exposed to treatments that modulated androgen action. Selectio n of genes was based on microarray studies and data reported in the literature (ie can didate genes). Chapter 1 Literature Review Page | iv The studies reported in this thesis show that neith er availability of androgens nor the AR are important in determining onset of the MPW, and providing exogenous androgens either prior to or during the MPW does not advance or nhance masculinisation. These studies also showed that females may have a slightl y different window of susceptibility to androgen action than do males. Key AR co-regulat ors have been characterized in the male reproductive tract for the first time, two of which (BRG1, CBP) show changes in expression through development of the testis consis tent with a role in Sertoli cells. Another AR co-regulator, RWDD1, was found to switch off in the absence of androgen action in the genital tubercle, pointing to a poten tial role during and/or after the MPW. Studies involving gestational exposure to indometha cin (a compound which inhibits prostaglandin synthesis) during the MPW showed no d etectable effect on masculinisation. Finally, evaluation of candidate g enes for mediating androgen action in the genital tubercle during the MPW, failed to iden tify their key involvement, thus they are unlikely to be involved in penis development an d disorders such as hypospadias. Chapter 1 Literature Review Page | v Presentations relating to thesis Poster Presentation at 5th Workshop on Endocrine Di sruptors 2011, Copenhagen, Denmark: ‘Molecular mechanisms of androgen induced programmi ng of masculinisation in the fetal rat genital tubercle’. Oral Presentation at Testis workshop, 2010, Elba, I taly: ‘Regulation and importance of the masculinisation programming window. ’ Oral Presentation at Andrology Conference, 2010, At hens, Greece: ‘Androgen molecular mechanisms involved in regulation of the masculinisation programming window’. Poster Presentation at 6th Workshop on Endocrine Di sruptors 2011, Copenhagen, Denmark: ‘ Investigations of the mechanisms underlying androge n action in the masculinsation programming window (MPW). Dean, A, Smith, L, Sharpe, R.M: The effect of dihydrotestosterone exposure during o r prior to the masculinisation programming window on reproductive development in male and female rats , Int J Androl. 2012 Jan 17 Chapter 1 Literature Review Page | vi