Origin of Human Chorionic Gonadotropin (hCG)
hCG is produced primarily by trophoblastic cells of the placenta, specifically by the syncytiotrophoblast (the endocrine tissue of the human placenta) and invasive extravillous trophoblast cells. 1
Primary Sources of hCG Production
Normal Pregnancy
- The syncytiotrophoblast is the main source of hCG secretion into maternal blood, where levels peak around 8-10 weeks of gestation 1, 2, 3
- hCG becomes detectable in maternal blood approximately 6-9 days after conception, initially rising above 5 mIU/mL to confirm pregnancy 1, 4
- The invasive extravillous trophoblast also secretes hCG, particularly hyperglycosylated forms (hCG-H) during early first trimester corresponding to the trophoblastic cell invasion process 2, 3
- hCG is produced by differentiated syncytiotrophoblast cells and functions primarily to maintain progesterone secretion by the corpus luteum until the placenta produces it independently 2, 5
Gestational Trophoblastic Disease
- All forms of gestational trophoblastic disease (GTD) are derived from components of the normal human placenta, representing abnormal counterparts of villous and extravillous trophoblast 1
- Choriocarcinoma consists of malignant hCG-producing epithelial tumors with differentiation toward a villous trophoblast phenotype 1
- Complete and partial hydatidiform moles produce hCG from abnormal trophoblast proliferation 1
- Placental site trophoblastic tumors (PSTT) form from extravillous interstitial implantation site-like trophoblast and produce lower hCG levels than choriocarcinoma 1
Different hCG Variants and Their Sources
Regular hCG
- Produced by differentiated syncytiotrophoblast cells during normal pregnancy 6
- Functions primarily to maintain the myometrial and decidual spiral arteries throughout pregnancy 6
Hyperglycosylated hCG (hCG-H)
- Made by undifferentiated cytotrophoblast cells, specifically extravillous cytotrophoblast cells 6
- Elevated during early first trimester and in choriocarcinoma cells 2, 3
- Stimulates trophoblast invasion and angiogenesis by interacting with TGFβ receptor 2, independent of LH/CG receptor signaling 2, 3
Free Beta-Subunit (hCGβ)
- Produced by a high proportion of malignancies, including nontrophoblastic tumors 6, 7
- Elevated serum levels observed in 45-60% of patients with biliary and pancreatic cancer and 10-30% of most other cancers 7
- Strongly associated with aggressive disease and poor prognosis in nontrophoblastic malignancies 7
Clinical Significance of Source Identification
- Genotyping can distinguish between gestational and non-gestational tumors that occasionally present as choriocarcinoma, such as lung and gastric cancers, which will have a genotype reflecting that of the patient rather than fetal tissue 1
- Non-gestational choriocarcinomas often initially respond to GTN-based therapies but have invariably poor outcomes, reflecting the originating tissue 1
- The interval from the causative pregnancy to GTN diagnosis carries prognostic information, making source identification through genotyping particularly helpful in patients with multiple pregnancies 1
Important Caveats
- hCG can be produced by non-pregnancy sources, including pituitary dysfunction or neoplasia, though this is rare 1
- Different glycoforms of hCG display different biological activities and functions depending on their source of production, which are essential for pregnancy outcome 2, 3
- The glycosylation state of hCG varies with the stage of pregnancy, its source of production, and in pathological conditions 2, 3