Although it is clear that human chorionic gonadotropin (hCG) and progesterone play fundamental roles in pregnancy, the regulation of placental production of these hormones remains to be defined. Recent evidence suggests that the human placenta expresses proteins related to inhibin (afi subunits) or activin (8P subunits). Inhibin and activin (folliclestimulating hormone-releasing protein) possess opposing activities in several biological systems including pituitary folliclestimulating hormone (follitropin) secretion, erythroid differentiation, and gonadal sex-steroid production. The actions of purified inhibin and activin on hormonogenesis by primary cultures of human placental cells were studied. The addition of activin increased gonadotropin-releasing hormone (GnRH) and progesterone production and potentiated the GnRHinduced release of hCG. Inhibin by itself did not modify placental immunoreactive GnRH, hCG, and progesterone secretion but reversed the activin-induced changes. Neither inhibin nor activin influenced the release of human placental lactogen. Furthermore, transforming growth factor (3, structurally related to inhibin/activin, did not signifcantly influence hormone release from cultured placental cells. These results support the hypothesis that inhibin and activin may play a role in regulating the release of GnRH, hCG, and progesterone from placenta and implicate inhibin-related proteins in the endocrine physiology of human pregnancy.Inhibins are heterodimeric proteins, consisting of an a subunit and one of two ,8 subunits (13A or PB), that were originally identified based upon their abilities to selectively suppress follicle-stimulating hormone (FSH) secretion (1-6). FSHreleasing proteins or activins were subsequently isolated and characterized as dimers comprised of inhibin (3 subunits APA or AJB) (7,8). Although inhibin and activin were first isolated from the gonads, various tissues including the placenta contain inhibin subunit mRNAs (9-12). Whereas the gonads contain a large excess of a-over (B-chain mRNAs, the placenta has an excess of p-subunit mRNAs; such observations raise the possibility that the placenta might have a preponderance of,,8 dimers (12). However, there is not yet conclusive evidence that intact activin is synthesized by human placenta.Placental inhibin a-subunit immunoreactivity is localized in the cytotrophoblast layer of the villi (11), a region shown earlier to contain other regulatory peptides including gonadotropin-releasing hormone (GnRH;, somatostatin (21), and corticotropin-releasing factor (22). The evidence that the placenta produces these hypophysiotropic peptides, which modulate the secretion of various hormones related to those in the pituitary [human chorionic gonadotropin (hCG), human placental lactogen (hPL), and corticotropin], supports the hypothesis that placental hormonogenesis may be regulated in part by locally produced peptides (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).A recent report (11) showed that the addition of inhibin antiserum increased hC...