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 birth. These disorders are interlinked and
may comprise a testicular dysgenesis syndrome (TDS), a concept supported by animal
model studies. The latter have identified the likely time-frame within which TDS
disorders may be induced, namely within the so-called masculinisation programming
window (MPW). During this critical period, sufficient testosterone (androgen) must be
produced by the fetal testis to program the male reproductive tract so that it will
differentiate and grow normally after the MPW. Impaired androgen production or action
within the MPW can result in smaller reproductive organs and their abnormal formation
and function (e.g. cryptorchidism, hypospadias).
The MPW is thus of fundamental importance in determining normal, or abnormal, male
reproductive development and function for later life. There are two big unanswered
questions about the MPW. First, what determines its timing? Second, what mechanisms
are controlled by androgens specifically within this 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 availability of androgens and or androgen
receptors (AR) plays a role in determining the onset or ‘opening’ of the MPW. Second,
investigation of whether the expression of AR co-regulators was a factor in determining
androgen sensitivity during the MPW. Third, investigation of whether prostaglandins
played a role in mediating androgen action in the MPW, as studies in the 1980s had
suggested this possibility. To address what mechanisms are controlled by androgens
specifically within the MPW, the expression of selected genes in the genital tubercle was
investigated before, during and after the MPW in fetuses that had been exposed to
treatments that modulated androgen action. Selection of genes was based on microarray
studies and data reported in the literature (ie candidate genes). The studies reported in this thesis show that neither 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 enhance masculinisation. These
studies also showed that females may have a slightly different window of susceptibility
to androgen action than do males. Key AR co-regulators 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 consistent 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 potential role during and/or after the MPW.
Studies involving gestational exposure to indomethacin (a compound which inhibits
prostaglandin synthesis) during the MPW showed no detectable effect on
masculinisation. Finally, evaluation of candidate genes for mediating androgen action in
the genital tubercle during the MPW, failed to identify their key involvement, thus they
are unlikely to be involved in penis development and disorders such as hypospadias