Category: receptor_pharmacology
The progesterone receptor (PGR, NR3C3) is a steroid nuclear receptor with two isoforms from a single gene via alternative promoters: PR-A (94 kDa, N-terminally truncated) and PR-B (114 kDa, full-length). The isoforms have distinct functions — PR-B is the major transactivator in uterus + mammary epithelium; PR-A often functions as a transdominant repressor of PR-B + ER + GR + MR. Genomic mechanism: progesterone binds cytoplasmic PR → conformational change → HSP90 dissociation → nuclear translocation → homodimerization → binds PRE (progesterone response element) → coactivator recruitment (SRC-1, p300) → transcription of target genes. Tissue effects: endometrium — secretory transformation, decidualization, pregnancy maintenance; mammary epithelium — alveologenesis, lactational priming; brain — anxiolytic + sedative via allopregnanolone metabolite (GABA-A positive allosteric modulator — NOT through PR; mechanism for PMS/PPD); cardiovascular — vasodilation, modest BP-lowering; immune — Th2 shift, immunosuppression of pregnancy. Non-classical (rapid, non-genomic) signaling: membrane PR (mPRα/β/γ/δ/ε = PAQR family) → Gi/o → ↓cAMP → second messengers in seconds-minutes; PGRMC1 (progesterone receptor membrane component) — cell survival + drug resistance. Anti-progestins: mifepristone (RU-486) — PR + GR antagonist, used for medication abortion (≤70 d) + Cushing syndrome (high dose); ulipristal acetate — SPRM (selective PR modulator), emergency contraception + uterine fibroids (UK withdrawn 2020 hepatotoxicity, EU restricted use). Progestins (synthetic PR agonists): levonorgestrel (LNG-IUD, EC, OC), norethindrone (POP, OC), drospirenone (Yaz — anti-androgen + anti-MR cross-reactivity → K⁺ retention), medroxyprogesterone acetate (DMPA injectable). Allopregnanolone-axis therapeutics: brexanolone (IV — postpartum depression, 60 h infusion), zuranolone (PO — same axis). Cross-links: [[steroid_hormone_biosynthesis]], [[gaba_a_receptor_signaling]] (allopregnanolone), [[hpg_axis]].