"The differentiation of the male and female genital phenotype is established at 7-12 weeks post conception. During this period, maintaining the appropriate intrauterine hormone environment is essential. However, it is surprising how little is known about the intrauterine hormonal milieu and the consequences of hormonal alterations. During her Marie Curie Intra-European Fellowship Dr Reisch’s work provided conclusive evidence for the existence of a novel androgen pathway in the fetal adrenal and its significance for the pathophysiology of oxidoreductase deficiency (ORD), a recently described form of congenital adrenal hyperplasia (CAH). The virilisation observed in CAH due to 21-hydroxylase deficiency (21-OHD), the most common form of CAH affecting 1:10,000 newborns, intricately ties the function of the fetal adrenal cortex to sexual differentiation of the external genitalia. To date, this has been explained by excessive production of adrenal androgens via the classic pathway to androgen synthesis during fetal and postnatal life. However, during fetal life, it is highly likely that the novel alternative pathway also plays a significant role in the pathogenesis of 21-OHD. The research of this grant application will investigate the impact of the newly discovered alternative pathway to fetal androgen biosynthesis on virilisation in 21-OHD via the analysis of the steroid metabolome in urines of pregnant mothers carrying babies affected with 21-OHD and affected newborns. Secondly, the project will elucidate the impact of the fetal adrenal-gonadal hormonal cross-talk on the development of testicular and ovarian adrenal rest tumors in 21-OHD in a model of 21-OHD deficient mice. These tumors are the most common cause of infertility in 21-OHD and current data suggest that they are primed during fetal development. This project has the potential of transfer of the results into patient care, e.g. with regard to refinement of prenatal treatment of CAH patients in the future."