Chapter 1.4 - Human chorionic gonadotropin: Different origins, glycoforms, and functions during pregnancy

Abstract

Human chorionic gonadotropin (hCG) is one of the first hormonal messages produced by the placenta toward the mother. Detectable in maternal blood 2days after implantation, hCG behaves like a superagonist of LH inducing the secretion of progesterone by the corpus luteum until the placenta itself acquires the ability to produce progesterone. hCG also has a role in quiescence of the myometrium and in local immune tolerance. Specific to humans, hCG is a complex glycoprotein composed of two highly glycosylated subunits. The α-subunit is identical to the pituitary gonadotrophin hormones (LH, FSH, TSH), contains two N-glycosylation sites, and is encoded by a single gene (CGA). The β-subunits are distinct in each of the gonadotropin hormones and confer receptor and biological specificity. hCGβ subunit is encoded by a cluster of genes (CGB), and the protein contains two sites of N-glycosylation and four sites of O-glycosylation. The expression of hCG and its glycosylation state vary with the stage of pregnancy, the source of production, and the pathology. The syncytiotrophoblast (ST) is the placental barrier between maternal and fetal blood that allows exchanges in nutrients and gases and also represents the endocrine tissue of the human placenta. Indeed, hCG is mainly secreted by the ST into maternal blood from about a week after fecundation reaching a peak around 8–10 weeks of gestation. Extravillous trophoblasts (EVTs), involved in chorionic villi anchoring, modulation of the uterine maternal immune system, and uterine artery remodeling, also secrete hCG. In particular, EVT produces hyperglycosylated forms of hCG (hCG-H) like in choriocarcinoma. In contrast to hCG, hCG-H is found elevated during early first trimester and then decreases, while hCG peaks. In addition to its endocrine role, hCG has autocrine and paracrine roles. It promotes the formation of the ST and angiogenesis through the LH/CG receptor but had no effect on trophoblast invasion. In contrast, hCG-H enhances trophoblast invasion and angiogenesis by interacting with the TGFβ receptor 2. hCG is largely used in antenatal screening and hCG-H represents a serum marker of implantation and early physiological trophoblast invasion. In conclusion, hCG is the main pregnancy hormone, whose maternal concentration and glycan structure change throughout pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome.