LHCGR

LHCGR is the class A GPCR on ovarian theca/luteal cells and testicular Leydig cells that converts the pituitary LH surge into steroidogenesis, ovulation, and luteinization - and in early pregnancy responds to placental hCG to maintain the corpus luteum. It is the direct downstream target after kisspeptin and GnRH drive the preovulatory LH surge. Activating LHCGR mutations cause familial male-limited precocious puberty and ovarian hyperstimulation syndrome; inactivating mutations cause Leydig cell hypoplasia and 46,XY DSD. LH and hCG analogs are approved fertility agents. Every scaffold for luteal support, male hypogonadism, or fertility pharmacology engages this target.

LHCGR (chromosome 2p21, ~699 aa) belongs to the glycoprotein hormone receptor subfamily with a large N-terminal ECD (~340 aa) containing nine leucine-rich repeats (LRRs) that form a horseshoe-shaped binding surface for the LH/hCG α-β heterodimer. Ligand specificity resides in LRRs 1–9, which recognize the LH/hCG β-subunit seat belt; a sulfated Tyr331 in the hinge region clasps the hormone as a molecular "thumb" to lock the complex. Ligand binding tilts the ECD ~48° toward the membrane and rotates a short hinge helix, releasing constraints on TM6. Outward TM6 displacement opens the intracellular G-protein docking cleft → Gs/adenylyl cyclase → cAMP → PKA → StAR/CYP11A1 → androgen and progesterone synthesis; ERK1/2 via SRC/EGFR transactivation drives cell proliferation and anti-apoptotic gene programs. hCG binds with higher affinity and slower dissociation than LH due to its extended C-terminal CTP region, explaining its use in corpus luteum rescue during early pregnancy. LHCGR shows higher constitutive activity than FSHR - a property exploited by intra-loop activating mutations (Asp564Gly) that cause hCG-independent Leydig cell activation in prepubertal males.

Approved agents: urinary hCG (Pregnyl, Novarel), recombinant hCG (choriogonadotropin alfa / Ovidrel) for IVF ovulation triggering; urinary LH (Luveris) and recombinant LH (lutropin alfa) for LH-deficient women in controlled ovarian stimulation; testosterone (multiple formulations) for downstream androgen replacement in LHCGR-deficient males. No selective LHCGR antagonist is approved - mifepristone blocks downstream progesterone signaling rather than the receptor. For peptide research, the tractable recipes are: hCG β-subunit loop peptides (particularly the β-hairpin loop 93–100) that activate LHCGR without triggering full hormone desensitization for luteal phase support; truncated hCG analogs lacking the CTP for rapid-clearance ovulation triggering with lower OHSS risk; LHCGR-selective small-molecule allosteric agonists (compound 3 and org 43553 series provide pharmacophore templates) for oral fertility support; and biased LHCGR agonists that selectively drive Gs/cAMP steroidogenesis over β-arrestin desensitization to extend luteal phase signaling per injection.