HCG

Human chorionic gonadotropin (hCG) is a glycoprotein hormone made by placental syncytiotrophoblast cells (Cole, 2010). It pairs a 92-residue alpha subunit, almost identical to that of luteinizing hormone (LH), with a 145-residue beta subunit, and carries sugar chains at two alpha and six beta positions (Morgan et al., 1975).

The alpha subunit is common to hCG, LH, follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) (Fiddes and Goodman, 1981), so the beta subunit gives hCG its identity. hCG and LH act through the same receptor, the LH/hCG receptor (LHCGR) (Duan et al., 2021).

PubChem name searches for hCG return unrelated small molecules, so no CID is listed.

The published work summarized here falls into five areas. Each summary below states the model used; human tissue, serum and drug products appear only as research history.

Subunits, genes and structure

Digests of human DNA suggested a single gene for the common alpha subunit, transcribed in the pituitary for LH, FSH and TSH and in the placenta for hCG (Fiddes and Goodman, 1981). The hCG beta subunit is unique in carrying a C-terminal extension with four serine-linked sugar chains. That extension and its sugars played a minor role in receptor binding and signaling in vitro, yet hCG with its beta subunit truncated after residue 114 was about 3-fold less active in vivo in rats (Matzuk et al., 1990).

In the crystal structure, each subunit folds around a cystine knot of three disulfide bonds, and a stretch of the beta subunit wraps the alpha subunit like a seat belt, fastened by the Cys26-Cys110 disulfide; the authors called this feature apparently essential for dimer association and receptor binding (Lapthorn et al., 1994). Models: cloned DNA, Chinese hamster ovary (CHO) cells, rats and X-ray crystallography.

The LH/hCG receptor (LHCGR)

The receptor was cloned from rat corpus luteum in 1989: a 341-residue extracellular domain with leucine-rich repeats joined to a 333-residue region with seven transmembrane segments. Cells expressing it bound hCG with high affinity and made more cyclic AMP (McFarland et al., 1989). Cryo-electron microscopy later captured LHCGR bound to chorionic gonadotropin and the stimulatory G protein (Gs), with the hormone pushing the extracellular domain and a conserved hinge segment acting as a tethered agonist (Duan et al., 2021).

LH and hCG share the receptor but do not signal identically. In COS-7 cells expressing it, recombinant hCG was about 5-fold more potent than LH on cyclic AMP while LH reached its maximal effect sooner, and in primary human granulosa cells LH gave more potent and sustained ERK1/2 and AKT activation (Casarini et al., 2012). Models: transfected cell lines, primary human granulosa cells and purified receptor complexes.

Placental origin and hCG variants

Immunohistochemistry placed hCG in syncytiotrophoblastic cells of immature placenta, hydatidiform mole, chorioadenoma destruens and choriocarcinoma, and detected none in cytotrophoblast (Midgley and Pierce, 1962). A 2010 review describes "hCG" as four molecules made by separate cells: hCG from villous syncytiotrophoblast, hyperglycosylated hCG from cytotrophoblast, a free beta subunit from some non-trophoblastic cancers, and a sulfated pituitary hCG made at low levels (Cole, 2010). Models: human placental and tumor tissue; a review.

Urinary and recombinant hCG

hCG drug products are purified from pooled human urine or made in genetically modified CHO cells. An HPLC and mass spectrometry study resolved 1,481 co-existing dimeric glycoforms in one recombinant hCG drug product and 1,167 glycoforms in one urinary product, and found that they differ considerably in glycosylation (Di Marco et al., 2023).

Those records cover drug products, not research material. Models: drug-product analysis; regulatory records.

How hCG is measured

The alpha subunit cannot tell hCG from LH, so specific assays target the beta subunit. An international workshop characterized 27 diagnostically relevant monoclonal antibodies against hCG: 21 were specific for the beta subunit, five for the alpha-beta dimer and one for the alpha subunit, and the authors judged low cross-reactivity with LH mandatory (Berger et al., 2002). Assays still differ in what they count.

In serum pools spiked with the WHO reference reagents and sent to laboratories over 7 years, 4 of 16 assays recognized only hCG, 6 also recognized the free beta subunit, and 6 recognized the beta-core fragment as well; the authors named this variable recognition the most important cause of method-related differences (Sturgeon et al., 2009).

Units differ too. Models: monoclonal antibody panels, spiked human serum and reference preparations.