Grant: Operating Grant

Androgens are considered as male sex hormones and they are normally produced by testis. On the other hand, we have demonstrated that they are produced in the developing lung of both sexes where they should play a physiological role. Consequently, how can the lung use androgens to regulate its normal lung maturation while higher levels of testosterone exist in male fetuses? This remains an open question. On the other hand, we have shown that the fetal lung expresses many of the adrenal gland genes in such a way that a hormone named 11-deoxycorticosterone (DOC) is produced. While DOC has glucocorticoid (GC) properties, we have shown that it is further transformed in the lung into 5alpha-DH-DOC, a molecule that has rather androgen properties. Based on our previous data showing that some cells of the lung can inactivate testosterone (but not 5alpha-DH-DOC) by an enzyme named 17beta-HSD2, we now start to understand the complex situation making of androgens efficient regulatory molecules in the lung. We hypothesize that 5alpha-DH-DOC plays a normal androgenic role in both sexes and that this is possible because 17beta-HSD2 keeps testosterone away from lung cells where 5alpha-DH-DOC plays a role of regulator. It is well documented that GCs can accelerate lung maturation while androgens "break" the action of GCs. In cases of high risks of premature birth, GCs are administered to mother about to deliver prematurely. This treatment accelerates lung maturation, but the problem is that many fetuses do not respond to antenatal GC. The present application aims to study DOC and 5alpha-DH-DOC synthesis and to accelerate lung maturation by administering an enzyme inhibitor that will block 5alpha-DH-DOC synthesis. This will decrease the amount of androgen-like molecules naturally produced by the lung itself and this is true for both sexes. We expect that this inhibitor will stimulate the action of glucocorticoids and, consequently, accelerate lung maturation.