Local actions of placental neurohormones and sex steroids have been proposed to play a role in the regulation of human chorionic gonadotropin (hCG) release from the human placenta. Accordingly, we utilized an in vitro perifusion system and cultures of placental explants to investigate short- and long-term effects of progesterone and its respective antagonist on hCG secretion from the human first-trimester placenta. Tissue slices (100 mg) obtained from legal pregnancy terminations of 9-12 weeks of gestation were continuously perifused and the effluent collected in fractions of 2-20 min. After initial perifusion periods of 30-140 min, either progesterone, a progesterone antagonist (ZK 98-299), or both were added to the perifusion medium at final concentrations of 10(-4)-10(-9) mol/l. Administration was either continuous or intermittent in 10-min pulses. Furthermore, 50-mg pieces of placental explants were cultured in multiwell tissue culture plates for up to 5 days. During the perifusion studies, hCG (determined by enzyme immunoassay) was released in a pulsatile fashion. This hCG pulsatility was decreased in response to both progesterone and progesterone antagonist at all concentrations tested. In contrast, intermittent administration of either treatment increased the hCG secretion. Secretion of hCG was not affected when progesterone and its antagonist were co-administered at equimolar concentrations. These observations demonstrate the diverging effects of progesterone and its antagonist on hCG secretion from the human first-trimester placenta in vitro, depending on the experimental conditions. Thus, progesterone-modulated hCG secretion appears to be regulated in a complex manner, its fine tuning involving other, as yet uninvestigated intraplacental factors.