ESTROGEN STIMULATION OF P450 CHOLESTEROL SIDE-CHAIN CLEAVAGE ACTIVITYIN CULTURES OF HUMAN PLACENTAL SYNCYTIOTROPHOBLASTS

The present study determined whether estrogen has a role in regulating the P450 cholesterol side-chain cleavage enzyme (P450(scc)) and/or de novo/deesterification cholesterol pathways involved in progesterone b iosynthesis within human syncytiotrophoblasts. Human placental syncyti otrophoblasts were cultured for 48 h with estradiol, and P450(scc) act ivity was determined by the formation of progesterone from 25-hydroxyc holesterol. Estradiol at 10(-7) or 10(-6) M and 25-hydroxycholesterol increased mean (+/- SE) progesterone production by syncytiotrophoblast s (ng/0.5 x 10(6) cells) to a value (19.2 +/- 1.1) that was 104% (p < 0.001) higher than that of the untreated controls (9.4 +/- 0.8) and 52 % higher (p < 0.001) than with 25-hydroxycholesterol alone (12.6 +/- 0 .9). The stimulation of progesterone secretion apparently was not the result of a change in progesterone metabolism to its principal metabol ite, because 20 alpha-hydroxypregn-4-en-3-one represented a minor secr etory component (0.7-1.7 ng/0.5 x 10(6) cells) under these conditions, and levels were not substantially altered by estrogen. In contrast to the stimulatory effect of estradiol on P450(scc) activity, estrogen d id not alter either the P450(scc) mRNA levels or the activities of 3-h ydroxy-3-methylglutaryl coenzyme-A reductase and cholesterol ester hyd rolase-rate-limiting enzymes for the de novo and deesterification path ways, respectively, for cholesterol formation in syncytiotrophoblasts in culture. Collectively, these results indicate that estrogen regulat es the P450(scc) component of the progesterone biosynthetic pathway, w hich we suggest signals functional/biochemical differentiation of sync ytiotrophoblasts during primate pregnancy.