Endocrine Abstracts

Mammalian differentiation of the external genitalia must be strictly dimorphic for reproductive success. In humans, this is established by a complex interplay of genetic and hormonal factors during 7–12 weeks post-conception (wpc). Despite being fundamental to normal human biology, understanding of human sexual differentiation remains limited. Our objective was to define the onset and regulation of androgen biosynthesis in the human fetal testis and correlate this to differentiation of the external genitalia.

Ethical approval was granted and informed consent gained from women undergoing voluntary first trimester termination of pregnancy. Leydig cells were identified in the fetal testis at 8 wpc by CYP11A, CYP17 and HSD3B2 expression. At this stage, the fetal testis robustly secreted testosterone in overnight culture (mean±S.E.M.: 299±56.4 nmol/l). Although Leydig cells expressed the LH receptor, the anterior pituitary demonstrated minimal LH immunoreactivity or secretion. Furthermore, testosterone secretion was only slightly increased by 10 μm forskolin (1.35±0.04 fold). These data indicate that early androgen secretion by the human fetal testis is largely constitutive. Surprisingly, during this period, the normal genitalia of both male and female fetuses expressed nuclear androgen receptor (AR). We have identified that the source of androgen, which induces AR nuclear localisation in female external genitalia, is the normal adrenal cortex. We investigated the consequences of this androgen activity on normal development by analysing forty AR candidate genes as a forerunner of expression microarray and ChIP-on-ChIP analyses (Myles Brown, Harvard Univ) to determine the widespread genetic and genomic consequences of AR function during sexual differentiation.

These data resolve debate on early human testosterone secretion by proving its constitutive nature. They demonstrate surprising indications of AR bioactivity during normal female development. Furthermore, they are anticipated to provide extended novel molecular insights into AR regulation and function during human sexual differentiation.