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(high dose); ulipristal acetate — SPRM (selective PR modulator), emergency contraception + uterine fibroids (UK withdrawn 2020 hepatotoxicity, EU restricted use).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.
Organ Systems
reproductive
nervous
endocrine
Pathway Steps
pregnenolone → progesterone (corpus luteum, placenta, adrenal) → circulating progesterone — via 3β-HSD on pregnenolone; ovarian + adrenal sources. Progesterone is synthesized from pregnenolone (itself from cholesterol) in the corpus luteum, placenta, and adrenal cortex. Luteal progesterone maintains early pregnancy until the placenta takes over — the basis for progesterone support in assisted reproduction and the target of antiprogestins (mifepristone).
progesterone → PR (cytoplasm, HSP90-bound) → activated PR — via HSP90 dissociation → homodimerization → nuclear translocation. Like other steroids, progesterone enters cells and binds the progesterone receptor, displacing HSP90 to yield an activated, dimerizing receptor. PR is itself an estrogen-induced gene, so PR expression marks estrogen-primed tissue — the logic behind PR status as a breast-cancer biomarker.
PR-A vs PR-B isoforms → differential PRE binding + tissue-specific transcription — via PR-A often transdominant repressor; PR-B major transactivator. PR exists as two isoforms from one gene — PR-B (a strong activator) and the shorter PR-A (often a repressor of PR-B and other steroid receptors). Their ratio varies by tissue and sets the net response, explaining progesterone’s opposite effects in, e.g., uterus versus mammary gland.
PR-PRE complex → target gene transcription — via SRC-1/p300 coactivator recruitment; chromatin remodeling. The activated PR binds progesterone response elements and recruits coactivators to drive genes that, in the uterus, oppose estrogen-driven proliferation and prepare the endometrium for implantation. This anti-estrogenic, differentiating action underlies the endometrial protection from progestins in hormone therapy.
progesterone (rapid) → membrane mPR (PAQR family) → Gi/o — via non-classical seconds-minutes signaling; distinct from nuclear PR. Progesterone also acts rapidly through membrane progesterone receptors (mPRs, the PAQR family) coupled to Gi/o — too fast for transcription. These non-classical receptors mediate effects in sperm, oocytes, and smooth muscle (e.g. myometrial quiescence), broadening signaling beyond the nuclear receptor.
progesterone (peripheral) → allopregnanolone (5α-reductase + 3α-HSD) — via → GABA-A positive allosteric — NOT through PR; mood effect axis. In peripheral tissues and brain, progesterone is reduced by 5α-reductase and 3α-HSD to allopregnanolone, a potent positive allosteric modulator of GABA-A receptors. This anxiolytic/sedative neurosteroid links progesterone fluctuations to mood (PMDD, postpartum) and is the basis of brexanolone for postpartum depression.