FSHR

FSHR is the glycoprotein hormone GPCR that drives ovarian folliculogenesis in females and Sertoli cell support of spermatogenesis in males - making it the primary molecular target for controlled ovarian stimulation in assisted reproduction. FSH/FSHR is also expressed in tumor-associated vasculature across multiple cancer types, making it a validated receptor for tumor-targeted peptide delivery. Activating mutations cause spontaneous ovarian hyperstimulation syndrome (OHSS); inactivating mutations cause primary ovarian insufficiency and male infertility. Every scaffold targeting fertility, gonadal function, or FSHR-positive tumor vasculature intersects this card.

FSHR (chromosome 2p16.3, 695 aa, ~75 kDa, 80–87 kDa after glycosylation) belongs to the leucine-rich repeat-containing GPCR (LGR) subfamily. The extracellular domain (ECD, ~350 aa) carries 11 LRRs in a horseshoe solenoid that provides high-affinity FSH binding (Kd ~1 nM); the FSHβ L2 loop engages the receptor LRRs while the FSH α-subunit contacts the hinge region. Upon binding, the ECD rotates ~48° relative to the TM bundle via a "push-and-pull" mechanism - FSHβ pushes against the membrane while the hinge helix pulls the ECD upright - propagating a ~14.9 Å outward shift of TM6 to open the G-protein docking cavity. Primary signaling: Gs → adenylyl cyclase → cAMP (5–20-fold elevation in granulosa cells) → PKA → CREB → aromatase, VEGF, anti-apoptotic gene expression. Secondary: Gβγ → ERK/MAPK via Src/EGFR transactivation; β-arrestin → non-canonical ERK; PI3K/Akt via APPL1. Receptor undergoes GRK2/3/5/6-mediated desensitization and β-arrestin recruitment. Glycosylation state of FSH tunes signaling: FSH21/18 (hypo-glycosylated) is ~10× more potent for cAMP than fully glycosylated FSH but shorter half-life.

Recombinant FSH preparations (follitropin alfa, follitropin beta, corifollitropin alfa - the latter a long-acting FSH-FSHβ CTP fusion with week-long duration) are approved for controlled ovarian stimulation and male infertility. No small-molecule FSHR agonist is approved, though Org 42599 and related thienopyr[im]idine derivatives reached clinical trials. For peptide research, the tractable recipes are: FSHβ-derived receptor-binding loop peptides that selectively engage FSHR without LH/CG cross-reactivity; biased FSHR agonists that preferentially activate β-arrestin/ERK over Gs/cAMP to separate the proliferative effects from steroidogenesis; and FSHR-targeting ligands conjugated to cytotoxins or radionuclides for tumor-vascular targeted therapy, leveraging FSHR overexpression in tumor neovasculature of prostate, breast, colorectal, and bladder cancers.