The aim of the study was to assess the effectiveness of progesterone (P) administered by nasal spray (NS) in inducing secretory changes within estrogen and non-estrogen primed postmenopausal endometrium. Ten healthy post-menopausal women before vaginal hysterectomy for prolapse were randomly treated by either oral estrogens for 3-4 weeks combined for the last 5-7 days with nasally administered P at the daily dose of 34 mg, or by only P for 6 days. Endometrial samples were taken before P administration and 8 h after the last dose. In the group not treated with estrogens, P did not induce significant secretory changes in any case except one which showed a proliferative endometrial pattern at the first evaluation. In the group treated with estrogens, in all the cases after P administration clear secretory changes (abundant vacuoles, endoluminal secretion) occurred. It is possible to conclude that P administered by NS exerts an end-organ effect within the endometrium of postmenopausal women pretreated with estrogens.