With the greatly increased popularity of segmented in vitro fertilization and frozen embryo transfers, progesterone replacement strategies in programmed cycles are being reexamined. Bidirectionality and the limited capacity of the uterine first pass provide an explanation for disconnects between the endometrial and serum levels when either vaginal or intramuscular progesterone is used alone. Whereas monotherapy departs from the physiology of spontaneous pregnancies, combined therapy provides physiologic replacement while minimizing the number of injections.