Location, location, location: A tubal neighborhood unfriendly to implantation

Reduced adrenomedullin secretion by tubal epithelial cells results in increased macrophage function and increased susceptibility to ectopic pregnancy. In a normal pregnancy, an oocyte is fertilized in the fallopian tube and is transported to the uterus, where it implants. However, in up to 2% of pregnancies the embryo implants elsewhere, most commonly in the fallopian tube. If a woman with a tubal ectopic pregnancy (TEP) is not treated in time, her fallopian tube can rupture, leading to disastrous consequences, including maternal death. One important risk factor for TEP is fallopian tube inflammation, termed salpingitis. However, why this condition leads to TEP is unknown, and there is no known method to prevent TEP in women with salpingitis. New research from Wang et al. brings us an important step closer to solving this important challenge. Before this study, we knew that the peptide hormone adrenomedullin (ADM) is abundant in the fallopian tube and has anti-inflammatory properties, but whether it helped prevent TEP was unknown. To answer this question, Wang et al. obtained fallopian tube samples from women undergoing hysterectomy for salpingitis, TEP, or other gynecological conditions. Samples from women with salpingitis or TEP expressed less ADM and contained more inflammatory M1 macrophages, which produce the cytokines interleukin-6 (IL-6) and IL-8, than those from healthy controls. In an in vitro assay, media from these macrophages induced fallopian tube cells to express implantation-associated molecules such as leukemia inhibitory factor and home box protein A10 and made them more susceptible to attachment by trophoblast spheroids. Conversely, addition of ADM reduced macrophage expression of IL-6 and IL-8 and reduced trophoblast spheroid attachment. In revealing that ADM helps prevent TEP by reducing fallopian tube inflammation and receptivity to implantation, this study suggests that ADM could be developed as a therapeutic to prevent TEP. One key limitation of this study is that the salpingitis group included women with the inflammatory disease endometriosis. The peritoneal fluid of such patients has increased concentrations of cytokines, which could reduce ADM action in the fallopian tube. This work should set the stage for future investigations into the detailed roles of tubal macrophages in vivo, which could lead to new discoveries with potential to translate to the clinic for the prevention of ectopic pregnancy.