We have previously shown that progesterone increased sulfate uptake in glandular epithelial cells of guinea pig endometrium. To investigate whether cAMP might be the cause of the progesterone effect on sulfate uptake, cAMP accumulation and the effect of cAMP on sulfate uptake were evaluated in cells treated with 17 beta-estradiol alone or with progesterone. Progesterone provoked an increase in the intracellular cAMP accumulation in cells treated with 17 beta-estradiol. Moreover, cAMP or forskolin elicited the same marked increase in sulfate uptake as that observed with progesterone. The effect of progesterone on sulfate uptake was abolished by blocking either the cAMP pathway or the genomic action of progesterone and was independent of the cAMP-activatable apical chloride channel. This study is the first evidence of cAMP activation of sulfate uptake and suggests a genomic effect of progesterone on the production of cAMP which activates the sulfate transport system in a short term activation and a long term activation independent of transcriptional or translational events. The endometrium is a unique tissue that undergoes profound highly regulated modifications during the secretory phase in providing a suitable environment for embryo implantation. The regulation of sulfate uptake could participate in this process.