Prostaglandin F2 alpha (PGF2 alpha) was identified as a luteolytic hormone in sheep (Nature, New Biol. 238, 129, 1972). Attempts to use PGF2 alpha for the pharmacological control of luteolysis in normal cycling sheep met with only partial success due to the rapid clearance of PGF2 alpha from the blood. In addition treated animals showed moderate to severe cardiovascular and gastrointestinal side effects. Accordingly, experiments were carried out to determine whether PG analogs might be more effective as pharmacological luteolytic agents. These compounds, which consisted of a number of the 13-dehydro analogs of PGF2 alpha, were administered to both sheep and monkeys either directly into the ovary or into the systemic circulation to examine them respectively for direct luteolytic activity and for resistance to metabolism. In addition in both the sheep and the monkey smooth muscle activity of the analogs was determined by recording uterine contractions in vivo. Several 13-dehydro analogs including some 16-fluoro derivatives were shown to have luteolytic activity equal to, or in some cases greater than, PGF2 alpha itself. Furthermore most of these compounds showed a marked resistance to the 15-OH-PG-dehydrogenase enzyme in vivo as evidenced by their luteolytic activity when infused intravenously. In terms of uterine contractions, several luteolytic analogs showed markedly diminished smooth muscle activity, and in some cases, complete absence of activity. These results suggest that the receptors governing the luteolytic effect on the one hand, and the smooth muscle effect on the other, possess different structural specificities. Recent studies which we have carried out on the effect of PGF2 alpha on corpus luteum (CL) blood flow support this conclusion. CL capillary blood flow was continuously monitored by means of a miniaturized Geiger-Müller probe inserted through the center of the CL in both the in situ and the autotransplanted ovary of the sheep. Capillary blood flow was measured by the clearance rate of 85Krypton injected periodically into the ovarian artery before and during the induction of luteolysis with PGF2 alpha. It was concluded that the initiation of luteolysis is not dependent on a smooth muscle effect of PGF2 alpha on the capillaries of the CL, a finding which supports the results with the synthetic analogs devoid of smooth muscle activity. More recently, in the primate model used (Macaca fascicularis) we have demonstrated that certain metabolically stable analogs are luteolytic when given intravenously, subcutaneously, or orally. These results demonstrate a rational approach to both drug synthesis and biological evaluation and suggest that a once-a-month contraceptive agent, based on a luteolytic analog of PGF2 alpha, devoid of smooth muscle activity (side effects) and metabolically stable in the bloodstream may become a reality.