Corticosteroid treatment of the fetus, which accelerates lung maturation, may mimic a modulating role of endogenous corticoids in normal development. To investigate this question, we determined the developmental pattern of plasma corticoids and their binding proteins in the rabbit, a commonly used species for studies of lung differentiation. The concentration of cortisol, the most potent glucocorticoid in the rabbit, was maximal at 23 days gestation (1.89 micrograms/dl), declining to 0.54 micrograms/dl at term (31 days). Levels of plasma corticosterone were always lower than those of cortisol. The adrenal content of corticoids, expressed per adrenal DNA or g BW, decreased during late gestation. Corticosteroid-binding globulin in fetal plasma decreased strikingly between day 23 (36 micrograms cortisol bound/dl) and day 31 (4.4 micrograms/dl; P less than 0.001), whereas maternal levels increased about 10-fold during this time. Free cortisol in the fetus increased between 21 and 23 days (0.041 micrograms/dl) and then decreased somewhat until after day 29 when there was an increase. To examine more directly the influence of endogenous glucocorticoids in the fetal lung, we assayed cortisol in extracts of purified lung nuclei as a reflection of receptor-cortisol complexes. The nuclear content of cortisol was constant between 23 and 30 days at levels (0.056-0.074 ng/mg DNA) comparable to those predicted from data for plasma free cortisol. Thus, in the rabbit, increases in plasma cortisol and nuclear receptor-cortisol complex are not temporally associated with the major events of lung development as in other species. We speculate that endogenous glucocorticoids may have a permissive or delayed influence on the lung during normal development in the rabbit.