Since cis-clomiphene citrate (CC) used for ovulation induction may affect embryo implantation during in vitro fertilization, direct effects of the drug on human endometrium were tested. Estrogenic and antiestrogenic effects were evaluated in vitro by measuring changes in prostaglandin (PG) output provoked by estradiol (E2), CC, and mixtures of E2 and CC; progestagenic effects were tested with E2 17 beta-dehydrogenase activity and glycogen accumulation as end points. In secretary endometrium, 10(-6)M CC about doubled the basal output of PGF2 alpha and PGE2; 10(-8)M E2 increased the production of these PGs 3-fold and 1.8-fold, respectively. The effects of E2 at this concentration were not diminished by the addition of CC, even at 100-fold molar excess, under conditions in which 10(-7)M progesterone or 10(-6)M 4-hydroxytamoxifen suppressed completely the action of the natural estrogen. In proliferative endometrium, 10(-8)M and 10(-6)M CC had no consistent effect on E2 17 beta-dehydrogenase activity or glycogen accumulation. These results demonstrate that, under in vitro conditions, CC can exert direct estrogenic effects on the endometrium but does not act as an antiestrogen or a progestagen.