ANDROGEN BIOLOGY TO FETAL LUNG DEVELOPMENT

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Respiratory distress syndrome (RDS), the leading cause of death and illness among premature infants, is due to pulmonary surfactant deficiency. Maternal glucocorticoid treatment, which stimulates fetal surfactant production, is the only preventive treatment for RDS. For unknown reasons, this therapy is only effective in about 50% of treated infants. Androgens in fetal circulation act as anti-glucocorticoids, inhibiting fetal lung maturation and pulmonary surfactant production. We have discovered that circulating fetal adrenal androgens are high in glucocorticoid-treated infants who develop RDS. We hypothesize that anti- androgens combined with glucocorticoids will be more effective than glucocorticoids alone for the prevention of RDS. Androgen-treated rabbit fetuses will be used as a model for persistent fetal adrenal androgen production to determine how androgens inhibit glucocorticoid-stimulated surfactant production in vivo. This model of androgen-inhibited surfactant production will be used to evaluate the ability of the natural anti- androgen progesterone to reverse the inhibition of glucocorticoid- stimulated surfactant production, since progestins can safely be used in human pregnancy. Progesterone analogs with varying degrees of anti- androgenic activity will systematically be evaluated in vitro and then in vivo. to develop the most rapid-acting, biologically effective anti- androgen to reverse the inhibitory actions of androgens on glucocorticoid- stimulated surfactant production. The anti-androgenic effects of these progestins will be compared with the potent anti-androgen Flutamide, which effectively reverses the androgen inhibition of glucocorticoid-stimulated surfactant production. The potential therapeutic benefits of the experimental hormone treatments will be determined by measuring the relative amounts of surfactant phospholipid and surfactant protein in fetal rabbit lung wash and tissue, and their rates of synthesis and mRNA expression. The effects of these experimental hormonal therapies on both glucocorticoid receptor mRNA expression and binding activity will also be evaluated, since this is a key regulator of hormone-dependent surfactant production. Since this receptor mechanism is common to all glucocorticoid- sensitive fetal organs, e.g. lung, brain, gut, heart, skin, our Long Term Goal is to develop a rapid, effective antenatal glucocorticoid therapy for all of these immature organs. The novel therapeutic approach represents a breakthrough in the clinical treatment for premature infants.