The endometrial effects of vaginal progesterone have been found to be unexpectedly reliable. This has led us to suspect that a local direct vagina-to-uterus transport or first uterine pass effect was the basis of the uterine targeting of vaginal progesterone. After vaginal administration of progesterone, uterine tissue concentration has been found to exceed by more than 10-fold the levels achieved by systemic administration, despite plasma levels in the latter case that were more than seven times higher. Similar differences in systemic-to-uterine tissue level ratios have been observed between oral and vaginal administration of danazol. Originally seen as a pharmacological advantage permitting the uterine targeting of vaginally administered substances, it is possible that the first uterine pass effect plays a physiological role in the control of uterine contractile activity through the prostaglandins contained in the semen.