{"paper_id":"c03b18e1-aeb3-4c13-8a78-f143581bf3c2","body_text":"https://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nJournal of \nEndocrinology\n236:3\nR169–R188Y Jiang et al. Retinoids and endometrium\n10.1530/JOE-17-0544\nREVIEW\nPhysiological and pathological implications of \nretinoid action in the endometrium\nYanwen Jiang1, Lu Chen 1, Robert N Taylor 2, Chunjin Li 1,* and Xu Zhou 1,*\n1College of Animal Sciences, Jilin University, Changchun, Jilin, China\n2Departments of Obstetrics and Gynecology and Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, Winston-Salem, \nNorth Carolina, USA\nCorrespondence should be addressed to X Zhou or C Li: xzhou65@vip.sina.com or llcjj158@163.com\n*(C Li and X Zhou contributed equally to this work)\nAbstract\nRetinol (vitamin A) and its derivatives, collectively known as retinoids, are required for \nmaintaining vision, immunity, barrier function, reproduction, embryogenesis and cell \nproliferation and differentiation. Despite the fact that most events in the endometrium \nare predominantly regulated by steroid hormones (estrogens and progesterone), \naccumulating evidence shows that retinoid signaling is also involved in the development \nand maintenance of the endometrium, stromal decidualization and blastocyst \nimplantation. Moreover, aberrant retinoid metabolism seems to be a critical factor in \nthe development of endometriosis, a common gynecological disease, which affects up \nto 10% of reproductive age women and is characterized by the ectopic localization of \nendometrial-like tissue in the pelvic cavity. This review summarizes recent advances in \nresearch on the mechanisms and molecular actions of retinoids in normal endometrial \ndevelopment and physiological function. The potential roles of abnormal retinoid \nsignaling in endometriosis are also discussed. The objectives are to identify limitations in \ncurrent knowledge regarding the molecular actions of retinoids in endometrial biology \nand to stimulate new investigations toward the development potential therapeutics to \nameliorate or prevent endometriosis symptoms.\nIntroduction\nIn many species, such as human, nonhuman primates and \nrodents, the endometrium consists of epithelial glands \nsupported by a connective tissue stroma that undergoes \ncycles of proliferation and secretory activity. The uterine \nmucosa proliferates under the influence of estrogen. \nHowever, after ovulation, luteal progesterone changes the \nproliferative pattern to a secretory pattern that includes \ndecidualization of endometrial stromal cells, which \nprovides the nutritive and immune-privileged matrix for \nembryo implantation ( Gellersen & Brosens 2014 ) and \nprevents the malignant transformation of endometrial \nepithelium under unopposed estrogenic action ( Cheng \net  al . 2008 ). Though progesterone is critical for the \ninitiation and maintenance of decidualization in the \nestrogen-primed endometrium, other factors, including \nprostaglandins, prolactin, growth factors and extracellular \nmatrix proteins, are important.\nRetinoic acid (RA), the physiological active metabolite \nof vitamin A (retinol), controls multiple biological \nprocesses, including differentiation, apoptosis and cell \nsurvival, via its nuclear receptors RARs or nonclassical \nRA receptor peroxisome proliferator-activated  \n3\nKey Words\n f retinoids\n f endometrial stroma\n f implantation\n f endometriosis\nJournal of Endocrinology  \n(2018) 236, R169–R188\n236\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR170\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\nreceptor β/δ (PPAR β/δ). The pathway of RA is also \nconsidered to be involved in the proliferation of \nepithelia and the transformation of endometrial stromal \ncells into specialized decidual cells. Numerous studies \nhave demonstrated that the distribution of RA ( Zheng \net  al . 2000 ), as well as the expression of RA receptors \n(Fukunaka et al . 2001, Ozaki et al . 2017), cellular retinol \nand RA-binding proteins (CRBP1, CRABP1 and CRABP2; \nZheng & Ong 1998 , Zheng et al . 2000), RA-synthesizing \nenzymes ALDH1A1 and ALDH1A2 ( Napoli 1999, Duester \n2000), and the RA-catabolizing enzyme CYP26A1 (Vermot \net  al . 2000 ) are highly and differentially regulated in \nthe differentiating endometrium during the ovarian \ncycle and during the phase of blastocyst implantation \n(Vermot et  al . 2000 , Zheng 2000 , Ozaki et  al . 2017 ). \nThe expression of these same genes can be modulated \nby ovarian steroid hormones (i.e., estradiol and \nprogesterone) treatment ( Vermot et  al . 2000 , Li & Ong \n2003, Rühl et al.  2006, Fritzsche et al . 2007). The retinoid \npathway is known to play vital roles in endometrial \ndevelopment and differentiation ( Tanmahasamut & \nSidell 2005, Wu et al . 2013, Nakajima et al . 2016), as well \nas endometrial neovascularization ( Sidell et al . 2010) and \nblastocyst implantation ( Han et al . 2010, Xia et al . 2010, \nMa  et al . 2012 ).\nIn addition, accumulating evidence shows that an \naberrant RA metabolism can be a critical factor in the \ndevelopment of endometriosis (Pavone et al . 2011, Wieser \net al . 2012, Pierzchalski et al . 2014, Yamagata et al . 2015), \na common gynecological disease that affects up to 10% \nof reproductive-age women. This disease is characterized \nby the ectopic localization of endometrial-like tissues \nin the pelvic cavity, and its pathogenesis involves \nuncontrollable cell proliferation and is associated \nwith local invasion and distant metastasis. Among the \nnumerous aspects of endometrial behavior regulated by \nRA are matrix metalloproteinase secretion, gap junctional \nintracellular communication and the production of \nvarious cytokines involved in stromal cell growth, \nadhesion and differentiation (Wu et al . 2013). Interleukin \n6 (IL-6), monocyte chemotactic protein 1 (MCP-1), tumor \nnecrosis factor α (TNF- α), vascular endothelial growth \nfactor (VEGF) and connexin43 are all aberrantly expressed \nin endometriotic lesions ( Sawatsri et  al . 2000 , Sharpe-\nTimms 2001 , Nozaki et  al . 2006 , Sidell et  al . 2010 , Wu \net al . 2013). Thus, many seemingly discordant features of \nendometriosis, including decreased cell death, increased \ngrowth and migration, inflammation and enhanced \ninvasive properties of intraperitoneally seeded endometrial \ncells, might be accounted for by the dysregulation of RA \nsignaling. This contention was recently supported in \na mouse model of endometriosis where treatment with \nRA suppressed IL-6 and the establishment, growth and \nvascularity of peritoneal implants, promoted macrophage \ndifferentiation (Wieser et al . 2012).\nRA plays fundamental roles in the normal \nmaintenance of endometrial physiology ( Zheng \net  al . 2000 , Sidell et  al . 2002 , Ding et  al . 2003 , Kuroda \net  al . 2013 ), and aberrant RA metabolism might be a \npredisposing factor for the development of endometriosis \n(Pavone et al . 2011, Wieser et al . 2012, Pierzchalski et al . \n2014, Yamagata et al . 2015). However, a comprehensive \nand systematic analysis and understanding of RA \npathway in endometrial physiology and pathology \nremain lacking. In this review, the latest advances \nwith regard to understanding the retinoid pathway \nare first discussed, followed by an assessment of the \nfunctional roles of this signaling network in endometrial \ndevelopment and physiological function. This review also \nsummarizes evidence that supports fundamental defects \nin retinoid metabolism and action among women with \nendometriosis. The objectives are to identify limitations \nin our current knowledge regarding molecular retinoid \nactions in endometrial biology and to propose future \ninvestigations to develop therapeutic or preventative \nagents for clinical endometriosis management.\nRetinoid metabolism and signaling\nRetinol (vitamin A) is a lipid-soluble vitamin that cannot \nbe synthesized de novo by animals and is obtained from the \ndiet as either preformed retinoids or carotenoids within \nthe intestine. In the enterocytes, proretinoid carotenoids, \nsuch as β-carotene, can be either cleaved and converted \nto retinoids or incorporated intact and unmodified along \nwith dietary fat and cholesterol into chylomicrons. Dietary \nretinoids that are newly absorbed by the enterocytes are \nesterified to retinyl ester and packaged with dietary fat and \ncholesterol into chylomicrons, which are later secreted \ninto the lymphatic system. Approximately 66%–75% of \nnewly acquired retinoids are absorbed and stored in the \nliver as lipid droplet retinyl esters ( Harrison 2005 ). The \nremainder is absorbed by extrahepatic tissues ( Quadro \n2004). In cases of dietary vitamin A deficiency, the stored \nretinoid is hydrolyzed and mobilized back to retinol, \nwhich can be bound by RBP4 and enter the bloodstream \nfor transport to peripheral tissues. In blood, holo-RBP4 \nis bound to transthyretin (TTR), a carrier protein for \nthyroid hormones. In a fasting circulation, retinol-RBP4 \nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR171\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\nis the preponderant retinoid form comprising >95% of \nretinoids, whereas, after a retinoid-rich meal, chylomicron \nretinyl ester concentrations exceed those of retinol-RBP4. \nIn extrahepatic tissues, retinoids are acquired from the \ncirculation in the form of carotenoids and retinyl esters \nfrom chylomicrons and retinol from retinol-RBP4-TTR \nternary complexes. The uptake of retinol from retinol-\nRBP4-TTR into cells is mediated by the transmembrane-\nspanning protein stimulated by retinoic acid 6 (STRA6), \nwhich acts as a high-affinity cell surface receptor that \nbinds extracellular holo-RBP, facilitates the dissociation \nof retinol from its carrier and transports it into cells \n(Kawaguchi et al . 2007, 2015).\nWithin target cells, carotenoids and retinyl esters \ncan be both converted into retinol, which binds \ncellular retinol-binding proteins (CRBP1 and CRBP2). \nCellular retinol can be stored in the form of retinyl ester \ncatalyzed by lecithin: retinol acyltransferase (LRAT) or \nconverted into transcriptionally active RA metabolites \nvia two enzymatic reactions. First, retinol is converted \ninto retinaldehyde by alcohol dehydrogenases (ADHs) \nor retinol dehydrogenases (RDHs) ( Fig.  1 ). Aldehyde \ndehydrogenases (ALDHs) then catalyze the conversion \nof retinaldehyde into RA ( Conaway et  al . 2013 ). In the \nretinal pigment epithelium of the eye, retinol can also be \nmetabolized to 11-cis-retinal, which serves to regenerate \nthe visual pigment rhodopsin.\nMost of the physiologic actions of retinoids are \naccounted for by the transcriptional regulatory activity \nof physiological active metabolites, i.e., all-trans-retinoic \nacid (atRA or RA) and 9-cis retinoic acid (9cRA). The action \nof RA is mediated by nuclear receptors, RA receptors \nFigure 1\nSchematic representation of retinoid uptake, metabolism and signaling in endometrial stromal cells (ESC) and endometrial epithelial cells (EEC). ESC can \ntake up retinoids from the circulation in the forms of retinyl esters in chylomicrons (following a retinoid-rich meal), RBP4-bound retinol (ROH) (during \nfasting) or albumin-bound RA (very low levels). The transport of retinol from retinol-RBP4 into ESC is mediated by STRA6; however, the cellular processes \nthat mediate retinyl ester and RA uptake are not yet established. Carotenoids in chylomicrons also represent a source of retinoids and can be converted \nto retinal (Rald) by β-carotene-15, 15′-monooxygenase (BCMO1). Cellular retinol can be oxidized to retinal and RA by dehydrogenases (ADHs, RDHs and \nALDHs) or be converted to retinyl ester, a retinoid storage form, catalyzed by LRAT. Retinyl esters can also be hydrolyzed to retinol catalyzed by retinyl \nester hydrolase (REH). RA exerts autocrine and paracrine transcriptional regulatory effects through RARs, RXRs and PPARβ/δ or alternatively degraded by \nCYP26 enzymes in ESC and neighboring EEC. A full colour version of this figure is available at https://doi.org/10.1530/JOE-17-0544.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR172\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\n(RARs): RARα, RARβ and RARγ or peroxisome proliferator-\nactivated receptor β/δ (PPAR β/δ). In conjunction with \ntranscriptional coactivators and corepressors, RARs and \nPPARs heterodimerize with retinoid X receptors (RXRs: \nRXRα, RXR β and RXR γ) and associate with RA response \nelements (RAREs) or peroxisome proliferator response \nelements (PPREs) in the regulatory regions of specific target \ngenes to regulate target gene transcription ( Chambon \n2005, Schug et al . 2008, Al Tanoury et al.  2013, Rochette-\nEgly 2014 ). RA partitioning between the two receptor \nsignaling cascades has opposing effects on cell growth \nand apoptosis and the alternative pathways are regulated \nby the ratio of intracellular lipid-binding proteins, cellular \nRA-binding protein (CRABP2) and fatty acid-binding \nprotein (FABP5; Schug et al . 2007). CRABP2 and FABP5 can \nbind and transport RA to RARs and PPAR β/δ, respectively \n(Delva et al.  1999, Dong et al.  1999). Furthermore, besides \nclassical nuclear receptor signaling, RA stimulates rapid \nnongenomic signaling events through the stimulation \nof kinase phosphorylation by extra-nuclear RARs, which \nalso can affect gene transcription ( Al Tanoury et al . 2013, \nRochette-Egly 2014 ). The primary biological ligand for \nRARs is atRA, whereas 9cRA can bind to RARs and RXRs.\nThe tissue distribution and levels of RA are regulated \nthrough its synthesis by ALDHs ( Lin et al.  2003) and its \ncatabolism into inactive polar compounds by CYP26 \nenzymes ( Chithalen et  al.  2002 , Conaway et  al.  2013 ). \nCRABPs and FABP5 also participate in the regulation \nof RA concentration ( Dong et  al . 1999 , Noy 2000 ) and \nmetabolism (Delva et al . 1999, Dong et al . 1999, Napoli \n2016). In RA-sensitive tissues, CRABP1 can protect these \nvulnerable areas against the toxic effects of excessive \namounts of RA ( Ruberte et al . 1992). Furthermore, many \nof the components of RA biosynthesis are controlled \nby atRA via negative feedback. ATRA induces its own \ncatabolism by inducing CYP26 transcription, allowing \nthe degradation of excess atRA. Conversely, atRA can also \nregulate its biosynthesis by positive feedback, upregulating \nthe expression of several RA biosynthesis components, \nsuch as RBP4, CRBP1 and STRA6 (Wu & Ross 2010).\nRetinoid action in endometrial development \nand physiological function\nThe mammalian uterus develops from fused \nparamesonephric (Müllerian) ducts during embryonic \ndevelopment. The adult mammalian endometrium is \ndivided into two steroid-responsive compartments, \nnamely, an epithelial compartment consisting of luminal \nand glandular epithelia and a stromal compartment \nfilled with fibroblasts, microvascular cells, macrophages \nand perivascular and large granular lymphocytes that \ninfiltrate the stroma during the luteal phase of the \nmenstrual cycle ( Punyadeera et  al . 2003 ). Luminal \nepithelium is the first point of contact between the uterus \nand blastocyst during implantation, while glandular \nepithelia synthesize and secrete bioactive substances \nthat contribute to uterine receptivity and stromal cell \ndecidualization. The endometrial functional layer \nundergoes cyclic regeneration regulated by estradiol \nand progesterone during menstrual or estrous cycles. \nIt initially proliferates under the influence of estrogen. \nHowever, after ovulation, in addition to estradiol, the \novary starts to produce progesterone, which changes \nthe proliferative pattern to a secretory one, providing \na suitable environment for blastocyst implantation. \nFollowing fertilization, the embryo implants into the \nuterine wall and trophoblast-derived gonadotropins \nsupport the pregnancy by maintaining corpus luteum \nproduction of progesterone and estradiol. In this case, \nthe endometrial functional layer remains as decidua. \nIf  fertilization or implantation fails, the endometrium \nwill be either remodeled (estrous cycle) or shed (menstrual \ncycle). Numerous factors are involved in the regulation \nof endometrial development and function and RA plays \nimportant roles in these processes.\nHormonal control of endometrial retinoid pathway\nNumerous studies revealed that the retinoid pathway and \ndistribution of RA are distinctly and highly regulated in \nhuman and rodent endometrial epithelium and stroma \n(Vermot et al . 2000, Rühl et al . 2006, Fritzsche et al . 2007). \nThe biosynthesis of endogenous RA is catalyzed directly by \nALDHs. Among them, ALDH1A1 (also known as RALDH1) \nand ALDH1A2 (also known as RALDH2) exhibit specific \ntemporal and special expression patterns in human and \nrodent endometrium during the ovarian cycle and early \npregnancy. The abundance of Aldh1a1 mRNA increases \nduring murine diestrus and proestrus, whereas Aldh1a2 \nis highly induced in metestrus ( Vermot et al . 2000). The \ntissue localization of ALDH1A1 and ALDH1A2 showed \nthat ALDH1A1 and ALDH1A2 are expressed in glandular \nepithelial and stromal cells, respectively ( Vermot  et  al . \n2000). The highest Aldh1a2 expression in mouse stromal \ncells is observed during the estrogenic phase of the estrous \ncycle, strongly suggesting that its endogenous expression \nis estrogen dependent. This speculation was confirmed by \nsubsequent studies in the endometrium of mice, rats and \nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR173\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\nhumans (Deng et al . 2003, Li et al . 2004, Rühl et al . 2006). \nUsing ovariectomized mouse models, Rühl et  al . (2006)  \ndemonstrated that ALDH1A2 expression is rapidly (within \n1–4 h) induced in stromal cells by estradiol but not by \nprogesterone. By contrast, estradiol, but not progesterone, \ntreatment decreases (within 4–24 h) ALDH1A1 expression \nlevels in glandular epithelium (Rühl et al . 2006). In a study \nby Deng et al . (2003), ALDH1A2 expression was induced \nwithin human endometrium by estrogen replacement \ntherapy. Thus, estradiol stimulates ALDH1A2 expression in \nendometrial stroma but suppresses ALDH1A1 expression \nin the endometrial glandular epithelium. By contrast, \nprogesterone neither induces nor reduces the expression \nlevels of the two genes ( Table 1 ). The selective effects of \nestradiol are due to the differential expression of estrogen \nnuclear receptor isotypes ERα and ERβ (Katzenellenbogen \n& Korach 1997). In rat uteri, ER α is principally expressed \nin luminal and glandular epithelia, whereas ER β is \npredominantly expressed in the stroma (Mowa & Iwanaga \n2000a,b). As ALDH1A2 expression might be selectively \nregulated via ER β, further study should focus on using \nERα/ERβ-selective ligands to dissect these estrogen-\nregulated pathways in the regulation of ALDH expression. \nMeanwhile, a potential estrogen response element was \nobserved in the promoter of the mouse Aldh1a2 gene \n(Wang et al . 2001). However, whether it plays a functional \nrole remains unknown.\nIn addition to RA-synthesizing enzymes, RA levels are \nalso regulated by RA-catabolizing enzymes, particularly \nthe CYP26 family. These enzymes catalyze the conversion \nof RA into less-active polar metabolites ( Conaway et  al.  \n2013). CYP26A1, one of the most important members of \nthe CYP26 family, is expressed in female reproductive tract \n(Vermot et al.  2000). In endometrial tissue obtained from \npremenopausal women, the CYP26A1 mRNA levels were \napproximately 20 times higher during the late secretory \nphase than in the proliferative phase ( Deng  et al . 2003). \nIn mouse endometrium, although CYP26A1 expression \nis undetectable during the normal ovarian cycle, it is \nstrongly induced in luminal and glandular epithelia, 4 h \nafter progesterone administration ( Fritzsche et  al . 2007 ) \nor 24 h after human chorionic gonadotrophin (hCG) \nadministration ( Vermot et  al.  2000 ). Also, in mouse \nendometrial epithelium, Cyp26a1 expression is strongly \ninduced between 3.5 and 4.5 gestational days, i.e., when \nthe developing blastocysts implant into the endometrium. \nEndometrial Cyp26a1 expression can be mainly regulated \nby progesterone because not only Cyp26a1 mRNA levels \nare strongly increased in uterine luminal and glandular \nepithelial cells by the administration of progesterone or \nthe combination of progesterone and estradiol but also the \nsimultaneous administration of an antiprogestin inhibits \nthe gene expression ( Fritzsche et al . 2007) (Table 1 ). This \nregulation of Cyp26a1 expression by progesterone may \noccur through direct activation of the progesterone \nreceptor. RU486 (also known as mifepristone) is a \nsynthetic steroid that exerts antiprogesterone action \nby competing with progesterone for receptor binding \n(Chan et al . 2003). Treatment with either RU486 or the \ncombination of RU486 and progesterone showed an \ninhibition of Cyp26a1 expression ( Fritzsche et al . 2007). \nThe mouse Cyp26a1 promoter and its regulatory regions \nwere partially characterized by Loudig and coworkers \n(2000, 2005). Their study showed the presence of two \nRA response elements on the Cyp26a1 promoter, but no \nconsensus binding sites for progesterone receptors. Thus, \nfurther studies are necessary to identify the possible \nregulatory elements responsible for the progesterone \ncontrol of Cyp26a1 expression.\nSeveral binding proteins involved in the retinoid \npathway are also distinctive in rodent and human \nendometria during the ovarian cycle ( Loughney et  al . \n1995, Wardlaw et  al . 1997 ). Crbp1 expression peaked \nduring diestrus, whereas Crabp2 expression peaked \nTable 1 Upregulated and downregulated genes involved in retinoid metabolism and signaling by estrogen and/or progesterone \nin the endometrium.\nGenes E2 P4 E2+ P4 Cell type Species References\nALDH1A1 ↓a – Epithelium Mouse Vermot et al. (2000), Rühl et al. (2006)\nALDH1A2 ↑b – ↑ Stroma Human, mouse, rat Vermot et al. (2000), Deng et al. (2003), \nLi  et al. (2004), Rühl et al. (2006)\nCYP26A1 –c ↑ ↑ Epithelium Mouse Fritzsche et al. (2007)\nCRABP2 ↑ d Epithelium Mouse, rat Wardlaw et al. (1997), Li & Ong (2003)\nRARα ↑ Epithelium Rat Boehm et al. (1997)\nRARγ ↑ Epithelium Rat Boehm et al. (1997)\nRXRα ↑ Epithelium Rat Boehm et al. (1997)\naDownregulation; bupregulation; cno effect; d(blank) remains to be established.\nE2, estradiol; P4, progesterone.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR174\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\nsharply during estrus (proliferative phase). In addition, \nCrabp2 expression has been shown to be induced directly \nby estradiol administration in the uteri of ovariectomized \nrats ( Li & Ong 2003 ) ( Table  1 ). Immunohistochemical \nstudies showed that CRABP2 is localized to the luminal \nepithelium, whereas CRBP1 in the stroma (Wardlaw et al . \n1997). CRABP2 expression is associated with local RA \nlevels (Bucco et al . 1997, Zheng et al.  2000). From these \ndata, it can be concluded that the endometrial stroma \nupregulates ALDH1A2 and therefore RA production \nupon estrogen stimulation. RA then diffuses into the \nadjacent epithelium, where it is catabolized by CYP26A1 \ninduced by progesterone during the late secretory phase \nor implantation.\nNumerous studies demonstrated the expression of \nRARs and RXRs in human endometrial epithelial and \nstromal cells ( Prentice et al . 1992, Loughney et al . 1995, \nKumarendran et  al . 1996 , Fukunaka  et  al . 2001 ). Using \nNorthern blot, Kumarendran et  al. (1996) demonstrated \nthat RARβ mRNA expression is 1.7-fold higher in \nepithelial samples from the proliferative phase than from \nthe secretory phase. Meanwhile, no significant difference \nwas observed between the expression levels of RARα, RARγ \nand RXRα mRNA in epithelial tissues in the proliferative \nphase and those in the secretory phases. Similarly, the \nexpression of RARα, RARβ, RARγ and RXRα mRNA in human \nendometrial stroma did not change in the proliferative \nand secretory phases of the menstrual cycle (Kumarendran \net al . 1996). Meanwhile, using immunohistochemistry and \nWestern blot analysis, Fukunaka et al . (2001) investigated \nchanges in expression and subcellular localization of RARs \nand RXRs in human endometrial epithelium during the \nmenstrual cycle. Their results indicated that, in the nuclei \nof endometrial epithelia, RARs and RXRs are expressed \nstrongly in the proliferative phase and reduced during \nthe secretory phase, correlated with serum estradiol \nconcentration and ER expression ( Fukunaka et al . 2001). \nAlthough RXRs decrease during the secretory phase, \nthey are still expressed in the nuclei in the late secretory \nphase; by contrast, RARs are infrequently detected in the \nmidsecretory and late secretory phases ( Fukunaka et  al . \n2001). In stromal cells, the intensity of staining is strong \nin the proliferative phase but decreases in the secretory \nphase. Meanwhile, immunoreactivity to RXRs is strong \nthroughout the cycle, similar to that in the nuclei of \nthe epithelial cells ( Fukunaka  et  al . 2001 ). In addition, \nERα shows more intense staining in the endometrium of \nthe proliferative phase, and PR shows positive staining \nin the endometrium of the mid-proliferative and early \nsecretory phases ( Fukunaka  et  al . 2001 ). The expression \nof retinoid receptors is associated with serum estradiol \nconcentration and ER expression. Consistently, data \nfrom Boehm et  al . (1997)  showed that RAR α, RAR γ and \nRXRα expression levels are increased by estrogen in rat \nendometrial epithelium ( Table  1). Thus, the expression \nof RARs is strongly affected by serum estrogen via ER in \nthe endometrium. However, whether progesterone or PR \nexpression inhibits the expression of retinoid receptors in \nendometrium remains to be determined.\nTherefore, the endometrial retinoid pathway is \nmainly under the influence of ovarian steroid hormones, \nand RA and its receptors have regulatory effects on the \nendometrium during the ovarian cycle (Fig. 2 ).\nRetinoid action in endometrial differentiation and \ndevelopment\nFate determination of endometrium in Müllerian \nduct\nDuring development, the Müllerian ducts persist in \nfemales and differentiate into morphologically and \nfunctionally distinct oviducts, uterus and vagina. The \noviductal epithelia are composed of ciliated cells and \nsecretory cells ( Yamanouchi et  al . 2010 ); the uterine \nepithelia consist of simple columnar luminal and glandular \nepithelia (Kurita et al . 2000) and the vaginal epithelium \nFigure 2\nHormonal control of the retinoid pathway in the \nendometrium. Estradiol (E2) or E2 + progesterone \n(P4) can stimulate the expression of ALDH1A2, \nwhich can promote RA production, in stromal \ncells. RA produced by ESC can diffuse to EEC, \nwhere E2 can promote the expression of RARs, \nPPARβ/δ and CRABP2. Thus, E2 can increase RA \nsignaling in the endometrium. However, P4 can \ninhibit RA signaling through inducing CYP26A1 \nexpression in EEC. A full colour version of this \nfigure is available at https://doi.org/10.1530/\nJOE-17-0544.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR175\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\ndevelops into stratified cuboidal epithelium ( Nakajima \net  al . 2011 a). Nakajima et  al . (2011 a) performed tissue \nrecombination experiments with epithelium and stroma \nto investigate the mechanisms underlying differentiation \nof the Müllerian ducts. The data showed that stromal \nfactors determine the fate, differentiation and growth \nof Müllerian duct epithelia into the oviducts, uteri and \nvaginas of mice. DNA microarray analysis showed that \nthe expression of several genes involved in retinoid \nmetabolism is greater in the uteri than in the vaginas of \nneonatal mice (Suzuki et al . 2006, 2007). When pregnant \nrats are fed with a vitamin A-deficient diet, their fetuses \nexhibit incomplete Müllerian development ( Wilson & \nWarkany 1948). Furthermore, Müllerian ducts of RAR or \nRXR KO mice are absent at embryonic day 12.5 (E12.5) \n(Mendelsohn et al . 1994, Kastner et al . 1997). These data \nsuggest that retinoid signaling through RAR is essential \nfor Müllerian duct development.\nThe important role of the retinoid pathway in fetal \nuterine stroma development was identified in the mouse. \nIn fetal mice, Rdh10 and Aldh1a2 are expressed in the \nstroma of proximal Müllerian ducts, with expression \nlevels decreasing toward the caudal ends ( Nakajima et al . \n2016). RDH10 is the primary enzyme responsible for \ncatalyzing the conversion of retinol to retinaldehyde, \nthe first step of RA synthesis, in embryonic mice ( Farjo \net  al . 2011 ). Uterine Cyp26a1 expression is essential for \nblastocyst implantation in pregnant mice ( Han  et  al . \n2010). However, Cyp26a1 expression levels are low in \nMüllerian ducts, suggesting RA is not degraded there \nand more RA accumulates. Thus, RA levels might be \nincreased in proximal Müllerian ducts. This hypothesis \nwas confirmed in a reporter mouse expressing lacZ \nregulated by a strong RARE in the promoter. The data \ndemonstrated that the highest endogenous RA levels are \nin the proximal Müllerian duct stroma, and the levels \ngradually decrease from the proximal to caudal regions \n(Nakajima  et  al . 2016 ). Thus, RA is produced and acts \nin the stroma of proximal and middle Müllerian ducts. \nRdh10 and Aldh1a2 expression are significantly higher \nin the uteri of postnatal mice than those in their vaginas \nfrom postnatal day 2 (P2) to P90 ( Nakajima et al . 2016). \nMoreover, mice fed from birth with vitamin A-deficient \ndiets for 10 or 14 weeks exhibit squamous metaplasia in \ntheir uterine epithelia ( Darwiche et al . 1993, Jetten et al . \n1996). These data suggest a critical role of RA signaling in \nmaintaining uterine epithelium.\nIn organ-cultured Müllerian ducts of RARE-lacZ mice \nat E14.5 and E17.5, retinal or RA treatment stimulated RA \nsignaling in the stroma and induced uterine epithelial \ndifferentiation, which was defined as a layer of columnar \nepithelial cells negative for oviductal and vaginal epithelial \nmarkers. By contrast, inhibition of RAR signaling with \nthe pan-RAR antagonist AGN193109 (AGN; Nakajima \net  al . 2016 ) induces vaginal epithelial differentiation. \nNakajima et  al . (2016)  cultured Müllerian duct explants \nat E14.5 or E17.5 with RA or RAR antagonists and grafted \nthese under the renal capsules of host mice. At day 30 \npost grafting, control E14.5 Müllerian ducts developed \noviductal and uterine epithelia, while AGN treatment \nirreversibly induced vaginal epithelia. Meanwhile, grafted \nE17.5 middle Müllerian ducts had only uterine epithelia, \nand AGN treatment irreversibly induced vaginal epithelia. \nIn grafted E17.5 caudal Müllerian ducts, vaginal epithelia \nwere observed, and RA treatment permanently induced \nuterine epithelia but did not induce oviductal epithelia. \nThese data indicate that RA in stroma at developing stages \ninduces uterine epithelia in Müllerian ducts, whereas the \ninhibition of RAR signaling induces vaginal epithelia. The \nfate of oviductal stroma is determined at E14.5 (Nakajima \net al . 2016). In female mouse embryos, activin A induced \nby inhibin βA is essential for the differentiation of vaginal \nepithelia ( Nakajima et  al . 2011 b), whereas RA inhibits \ninhibin βA expression in the urogenital sinus ( Bryant \net al . 2014). Hoxa10 is expressed at the boundary between \nfuture uterine and oviductal stroma in the Müllerian \nducts at E16.5 (Ma et al . 1998) and is connected with the \ndetermination of the borderline between oviduct and \nuterus ( Benson et  al . 1996 ). RA stimulates  Hoxa10  and \nHoxa11 expression in Müllerian ducts; however, AGN \nabolishes these. Although the Hoxa10 promoter contains \na RARE ( Delacroix et  al. 2010), RAR cannot bind to the \npredicted RARE in the Müllerian duct ( Nakajima et  al . \n2016). Thus, RA seems to induce Hoxa10 expression via \nindirect RAR signaling, and other factors might mediate \nthe action of RA on the determination of the border \nbetween the uterine and vaginal stroma. These data \nsupport a model in which RA-RAR signaling can play a \ncrucial role in the determination of the fate of epithelia \nand stroma in the female reproductive tract (Fig. 3 ).\nEndometrial gland development\nUterine glands are essential for pregnancy on account of \nsecreting or transporting bioactive substances that regulate \nuterine receptivity and blastocyst implantation. Uterine \ngland development or adenogenesis is a postnatal event \nin rodents, domestic animals and humans (Hu et al . 2004). \nAt birth, murine uteri lack uterine glands and consist of \nsimple luminal epithelium supported by undifferentiated \nmesenchyme. Between P0 and P9, glandular epithelial \nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR176\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\ncells differentiate and bud from luminal epithelia. By \nP15, the uterine histoarchitecture resembles that of the \nadult ( Spencer et  al . 2012 ). Gland morphogenesis also \noccurs during endometrial regeneration following menses \nor parturition ( Garry et  al . 2010 , Huang et  al . 2012 ). \nBased on data from the available literature, the luminal \nand glandular epithelia of mouse uteri have common \nbut distinctly expressed genes ( Cha et al . 2012, Filant & \nSpencer 2013). The components of the retinoid pathway, \nincluding Aldh1a1, Aldh1a3, Rdh1 and Rdh10, are enriched \nin the glandular epithelia of neonatal uteri. Through \nmicroarray analysis, the glandular epithelium-enriched \ngenes in P10 uteri were found to be associated with \nbranching morphogenesis, growth and RA biosynthesis. \nAldh1a1 is enriched in developing neonatal and adult \nendometrial glands (Filant & Spencer 2013). Furthermore, \nthe expression levels of Aldh1a1 and  Aldh1a3  on P10 \nare much lower in progesterone-induced uterine gland-\nknockout (PUGKO) mice than in control mice ( Filant & \nSpencer 2013 ). In addition, retinyl palmitate increases \nglandular epithelial areas in the uteri of neonatal pigs \ntreated for 14 days starting from birth ( Vallet et al . 1995). \nThese data suggest that the retinoid pathway is involved \nin uterine adenogenesis. Further studies are still needed \nto elucidate the functional role of the retinoid pathway \nand the mechanisms governing uterine adenogenesis in \nneonates. The involvement of RA signaling in postnatal \nmouse endometrial adenogenesis will require conditional \npostnatal deletion models, such as the PR-Cre system.\nEndometrial proliferation\nOvarian estrogen induces the proliferation of epithelial \ncells and stromal fibroblasts during the pre-ovulatory \nphase ( Punyadeera et  al . 2003 ). Studies in rodents \nsuggested that RA plays an important role in modulating \nthe effects of estrogen on the endometrium. As discussed \nearlier, endometria upregulate ALDH1A2 upon estrogen \nstimulation during the proliferative phase ( Vermot et al . \n2000, Deng et al . 2003, Rühl et al . 2006). Furthermore, the \nexpression levels of RA receptors ( Fukunaka  et  al . 2001) \nand CRABP2 (Loughney et al . 1995, Wardlaw et al . 1997, \nLi & Ong 2003 ), which bind and deliver RA to nuclear \nRAR, are stimulated by estradiol in the proliferative \nphase in epithelial and stromal cells. These data suggest \nthat estrogen coordinately upregulates RA production, \ntransport and signaling in the proliferative phase of the \novarian cycle. This coordinated mechanism may play a role \nin antiproliferative effects that counterbalance estrogen-\ninduced endometrial proliferation. Studies on vitamin \nA-deficient rats demonstrated that physiologic levels of \nRA suppress endometrial hyperplasia and metaplasia \nassociated with chronic estrogen administration \n(Bo  &  Smith 1966 ). In addition, pharmacological doses \nof RA in immature ovariectomized rat suppress estrogen-\ninduced endometrial cell proliferation ( Boettger-Tong \n& Stancel 1995 , Loughney & Redfern 1995 ). This might \nbe a beneficial suppressive effect on estrogen-induced \nendometrial proliferation. RA can also effectively suppress \nthe estrogen-stimulated proliferation of breast cancer \ncells and in several endometrial carcinoma lines ( Carter \net  al . 1996 , Toma  et  al . 1997 ). Targeting physiological \nRA accumulation in the endometrium by estradiol is a \npotential suppressor mechanism to prevent malignant \ntransformation of hyperplastic endometrial cells during \nthe ovarian cycle and gestation. In the case of vitamin \nA deficiency, uterine epithelium forms regions of \nFigure 3\nSchematic representation of retinoid action in \nendometrial development and physiological \nfunction. RA signaling in the Müllerian duct \ndetermines the differentiation of epithelium to \nform the future uterus and vagina involving \nHoxa10, inhibin βA and activin A. Besides, \nRA signaling stimulates endometrial GJIC \nformation through inducing Cx43 expression and \nneovascularization through inducing VEGF \nexpression. RA prevents stromal cell \ndecidualization through inhibiting PRL, IGFBP1 \nand HSD11B1 production and promotes \nmaintenance of fibronectin, an indicator of the \nundifferentiated stromal phenotype. In addition, \nRA reduces factors like LIF and HB-EGF1, which \nare required for endometrial receptivity, and \nsuccessful implantation during late secretory \nphase requires lower RA levels in the luminal \nepithelia. A full colour version of this figure is \navailable at https://doi.org/10.1530/JOE-17-0544.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR177\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\nkeratinized squamous metaplasia, indicating that RA is \nneeded to maintain simple columnar uterine epithelium \n(Ponnamperuma et al . 1999).\nGap junction intercellular communications\nDecidualized stromal cells not only acquire epithelioid \nstructure and function, accumulating glycogen, lipids \nand subcellular organelles ( Lawn et  al . 1971 ) but \nalso express interdigitating lamellar processes within \nclustered microdomains called gap junctions. These gap \njunctions act as membranous channels for the direct \nexchange of small molecules (e.g., second messengers) \namong adjacent cells or between these cells and their \nextracellular environments ( Yamasaki et  al . 1999 ). Gap \njunction intercellular communications (GJIC) are critical \nto the success of decidualization because their blockade \nsuppresses the proliferation and differentiation of uterine \nstromal cells (Yu et al . 2011, Diao et al . 2013, Yu et al . 2014a, \nWinterhager & Kidder 2015 ). Connexin (CX) proteins \nare the major components of gap junctions, and CX43 \n(also known as GJA1) is the predominant CX protein in \nendometrial stromal cells ( Jahn et al . 1995, Winterhager \net  al . 2009 ) and undergoes a variety of changes during \nthe ovarian cycle ( Mantena et al . 2006). The attenuation \nof CX43 expression disrupts GJIC between neighboring \ncells and impedes the differentiation of stromal cells \nin human and mouse endometrium ( Laws et  al . 2008 , \nYu et  al. 2011). Endometrial CX43 may be regulated by \nhormonal changes, and the progesterone and estrogen \nlevels in serum are reported to determine the expression \nlevels of CX43 in the endometrium ( Yu et  al . 2014 b, \nWinterhager & Kidder 2015 ). RA and other retinoids \nenhance GJIC and CX43 expression levels in numerous \ncell types, certain human cancer cell types, mouse \nfibroblasts and rat liver cells, through transcriptional \nand translational mechanisms ( Stahl & Sies 1998 , \nCarystinos et  al . 2001 ). When treated with RA, CX43 \nexpression in human endometrial stromal cells shows a \ndose-dependent increase at the mRNA and protein levels \n(Tanmahasamut & Sidell 2005 ) ( Table  2 ). Concomitant \nwith the increase in CX43 expression, stromal cells treated \nwith RA exhibit a 2.5-fold enhancement in their GJIC as \nassessed by dye transfer experiments ( Tanmahasamut \n& Sidell 2005 ). The ability of endometrial stromal cells \nto serve as an RA-responsive target is supported by the \npresence of RA nuclear receptors (i.e., RARs and RXRs) \nin these cells ( Prentice 1992 , Comptour et  al . 2016 ). In \naddition to its expression level, the phosphorylation \nstatus of CX43 influences GJIC, including gap junction \nassembly and channel gating ( Solan & Lampe 2009 ). In \nendometrial tissue, phosphorylation of CX43 mostly \nimpairs GJIC ( Tanmahasamut & Sidell 2005 , Wu et  al . \n2013). Phosphorylation of CX43 is mediated by two \nserine/threonine protein kinase families, protein kinase \nC (PKC) ( Oh et al . 1991) and MAPK ( Warn-Cramer et al . \n1996). RA induced the CX43 de-phosphorylation at serine \n262 in human endometrial stromal cells ( Tanmahasamut \n& Sidell 2005 , Wu et  al . 2013 ). RA antagonized the \neffects of 12-O-tetradecanoylphorbol-13-acetate (a PKC \nactivator) and inhibited PKC activity in numerous cell \nsystems (Cope 1986, Verma 1988, Nakagawa et al . 2003), \nalthough the activation of PKC activity by RA has also \nbeen reported ( Kambhampati et  al . 2003 ). Inhibition of \nMAPK activity by RA was previously reported ( Nakagawa \net  al . 2003 ). The signaling pathway(s) involved in the \nCX43-dephosphorylating effects of RA remains to be \nelucidated, but protein phosphatase 2 has been implicated \n(Wu et al . 2013). Overall, these data support that retinoid \nsignaling can enhance GJIC among endometrial stromal \ncells ( Fig. 3 ).\nEndometrial neovascularization\nIncreased vascular permeability and angiogenesis are \nvital to the successful stromal decidualization, embryo \nTable 2 Effect of RA on the production of factors in the endometrial cells.\nFactors Regulation Cell type Species References\nCX43 ↑ Stromal cells Human Tanmahasamut & Sidell (2005), Wu et al. (2013)\nVEGF ↑ Stromal cells Human, mouse Matsumoto & Sato (2006), Sidell et al. (2010)\nPRL ↓ Stromal cells Human Brar et al. (1996), Ozaki et al. (2017)\nIGFBP1 ↓ Stromal cells Human Brar et al. (1996), Ozaki et al. (2017)\nHSD11B1 ↓ Stromal cells Human Ozaki et al. (2017)\nFibronectin ↑ Stromal cells Human Brar et al. (1996)\nLIF ↓ Epithelial cells Mouse Ma et al. (2012)\nHB-EGF1 ↓ Epithelial cells Mouse Ma et al. (2012)\nHSD17B2 ↑ Epithelial cells Human Cheng et al. (2008), Yamagata et al. (2015), \nPavone et al. (2017)\n↑, Upregulation; ↓, Downregulation.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR178\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\nimplantation and placentation (Dey et al . 2004, Matsumoto \n& Sato 2006, Wang & Dey 2006, Matsumoto et al . 2007). \nVEGF, originally reported as a vascular permeability factor, \nis also a potent mitogen for endothelial cells and a key \nregulatory growth factor for vasculogenesis or angiogenesis \n(Ferrara et al . 1997). In human endometrial stromal cells, \nRA can combine with transcriptional activators of VEGF to \nstimulate the expression and secretion of VEGF through \na translational mechanism mediated by reactive oxygen \nspecies (ROS; Sidell et  al . 2010 ) ( Table  2 ). In addition, \nGJIC plays a key role in endometrial neovascularization. \nThe conditional deletion of CX43 genes in stromal cells \nand the consequent disruption of GJIC result in the \nreduction of VEGF production and striking impairment \nin the development of new blood vessels within stromal \ncompartments (Laws et al . 2008, Yu et al . 2011). Notably, \nCX43 overexpression promotes VEGF secretion ( Yu et al . \n2016). As discussed earlier, retinoid signaling can enhance \nGJIC among endometrial stromal cells by stimulating \nCX43 expression and dephosphorylation. Thus, retinoid \nsignaling might promote neovascularization by enhancing \nstromal CX43 expression and GJIC. Evidence showed \nthat COX-2-derived prostaglandins participate in uterine \nangiogenesis during implantation and decidualization \n(Matsumoto et  al . 2002 ). In Cox-2 KO mice, failure of \nimplantation and decidualization are primarily due \nto defects in VEGF signaling. cPGI (an analog of PGI 2) \ntogether with 9cRA improves poor implantation in  \nCox-2(− /− ) mice. Moreover, the administration of cPGI \nand 9cRA restore the expression of VEGF and angiogenesis \n(Matsumoto & Sato 2006 ). In addition, Saito et  al . \n(2007) examined RA effects on in vitro capillary-like tube \nformation using human umbilical vein endothelial cells \nand demonstrated that RA as well as RAR agonist Am80 \nsignificantly induced capillary-like tube formation. \nThe RA-induced tube formation was inhibited by RAR \nantagonist. Meanwhile, the RA-induced tube formation \nwas completely abolished by coincubation with VEGF \nantibody or with VEGF receptor (VEGFR)-2 antibody, but \nnot VEGFR-1 antibody (Saito et al. 2007). These data provide \nevidence that although ovarian steroid hormones primarily \ninfluence uterine vascular permeability and angiogenesis \nduring the preimplantation period, RA-RAR signaling \nparticipates by regulating VEGF production (Fig. 3 ).\nStromal decidualization\nStromal decidualization denotes the transformation of \nmesenchymal stromal cells into specialized decidual \ncells, which acquire epithelioid structure and function, \naccumulating glycogen, lipids and subcellular \norganelles ( Lawn et  al . 1971 ) in part through a process \nof mesenchymal-epithelial transformation ( Yu et  al . \n2016). Decidual cells provide the nutritive and immune-\nprivileged matrix that is required for blastocyst \nimplantation and placental formation in mouse and \nhuman uteri (Zhang et al . 2013, Gellersen & Brosens 2014). \nPerturbed or inadequate decidualization leads to embryo \nmiscarriage and early pregnancy failure (Kommagani et al . \n2013). Accompanied by typical morphological changes, \ndifferentiating stromal cells express biochemical decidual \nmarkers, such as prolactin (PRL), insulin-like growth \nfactor-binding protein-1 (IGFBP1) ( Irwin et  al . 1994 , \nBrar et al . 1997) and 11 β-hydroxysteroid dehydrogenase \ntype 1 (11 βHSD1) ( Brosens et  al . 1999 , Kuroda et  al . \n2013). Data from Ozaki et al . (2017) showed that RARs, \nas well as CRABP2 and FABP5, which are responsible \nfor binding and delivering RA to nuclear receptors RARs \nand PPAR β/δ respectively, decreased in decidualizing \nhuman endometrial stromal cells despite an increase in \nPPARβ/δ. Besides, decidualization was also associated with \nincreased expression of CYP25A1 ( Table 3 ). In addition, \nexposure of differentiating stromal cells to 10 nM RA or \nretinal prevents the inhibition of the RAR pathway and \nperturbs expression of PRL, IGFBP1 and 11 βHSD1 (Ozaki \net al . 2017). Brar et al . (1996) consistently demonstrated \nthat RA treatment suppressed PRL and IGFBP1 production \nand promoted maintenance of fibronectin, an indicator \nof the undifferentiated stromal phenotype (Yu et al . 2016) \n(Table 2 ). Though PPARβ/δ and RXRs are highly expressed \nat implantation sites in human and rat endometrium \n(Fukunaka et al . 2001, Ding et al . 2003) and endometrial \nstromal cells can synthesize RA from retinol during \ndecidualization and blastocyst implantation ( Ulven et al . \n2000, Deng et al . 2003), no evidence exists that RA, even \nat low concentrations, promotes stromal decidualization, \nat least not when assessed by the induction of responsive \nTable 3 Upregulated and downregulated genes involved in \nretinoid metabolism and signaling in decidualizing \nendometrial stromal cells.\n \nGenes\nUpregulation or \ndownregulation\n \nSpecies\n \nReferences\nRBP4 ↑ Human Ozaki et al. (2017), \nPavone et al. (2017)\nCYP26A1 ↑ Human Ozaki et al. (2017)\nCRABP2 ↓ Human Ozaki et al. (2017), \nPavone et al. (2017)\nFABP5 ↓ Human Ozaki et al. (2017)\nRARα ↓ Human Ozaki et al. (2017)\nPPARβ/δ ↑ Human Ozaki et al. (2017)\n↑, Upregulation; ↓, Downregulation; E2, estradiol; P4, progesterone.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR179\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\ndecidual markers (PRL, IGFBP1 and HSD11B1). At high \nconcentrations, RA decreases cell viability and exhibits \ntoxic effects ( Ozaki et  al . 2017 ). These data suggested \nthat RA signaling is attenuated upon decidualization, \nand RA treatment suppresses the decidualization and \ncontributes to the maintenance of stromal cells in an \nundecidualized state. Furthermore, RA was suggested to \nprevent the increase in intracellular cAMP accumulation \nin stromal cells that occurs during the induction of \ndecidualization in vitro  with progesterone and estradiol \n(Brar et al . 1996). Meanwhile, the activation of the cAMP \nsignal pathway is essential and sufficient to induce PRL \nproduction in endometrial stromal cells ( Tang et  al . \n1993, Gellersen et  al . 1994 ), and inhibition of PRL \nproduction by RA cannot be restored by cAMP treatment \n(Brar et  al . 1996 ). The inhibition of intracellular cAMP \nproduction by RA is a plausible mechanism by which RA \nsuppresses stromal decidualization. On the other hand, \nendogenous RA biosynthesis from retinol is increased \n1.4-fold in endometrial stromal cells subjected to in vitro \ndecidualization compared to control cells ( Sidell et  al.  \n2010). Thus, more precise dose-response relationships \nshould be established to fully understand the possible \ndifferential effects of RA signaling via the opposing \nCRABP2-RAR vs FABP5-PPARβ pathways.\nRetinoid signaling in blastocyst implantation\nIn humans and rodents, implantation occurs via successive \nblastocyst apposition, attachment, and adhesion to the \nreceptive luminal epithelium, followed by the penetration \nand invasion of trophectoderm into the decidualized \nstroma ( Dey  et  al . 2004 ). Successful implantation \nrequires not only a receptive endometrium but also a \npreimplantation blastocyst temporally competent to \nengage in precise crosstalk with the maternal endometrial \nsignals. Recent evidence suggested that two separate \nuterine signals during blastocyst implantation. One signal \nprimes the trophectoderm for attachment to the luminal \nepithelium, and the other results in the uptake of amino \nacids by the blastocyst, the motility of which is initiated \nfor invasion ( Gonzalez 2012 ). Signaling of endometrial \nreceptivity to blastocyst attachment involves the actions \nof ovarian steroid hormones on the luminal epithelia and \nparacrine factors expressed by different endometrial cell \ntypes (Cha et al . 2012, Zhang et al . 2013).\nRodent studies demonstrated that the tight regulation \nof retinoid pathways play crucial roles in maintaining \nuterine receptivity and blastocyst implantation ( Osteen \net al . 2003, Han et al . 2010). In mice, the uterus becomes \nreceptive to blastocyst implantation by the afternoon of \ngestational day 4 but is refractory by the afternoon of day \n5 (Zhang et al . 2013). No Cyp26a1 mRNA was found in \npreimplantation endometrium, while its expression was \nspecifically induced between 3.5 and 4.5 gestational days, \ni.e.,  the implantation period, was localized in luminal \nepithelia ( Vermot et  al . 2000 , Han  et  al . 2010 ). The \nspecific spatiotemporal expression pattern of Cyp26a1 \nin preimplantation endometrium suggests that it is \ninvolved in blastocyst attachment and/or invasion to the \nendometrium but not in the initial preparations of the \nendometrium. This hypothesis was supported by data in \nwhich the number of implantation sites was significantly \nreduced when Cyp26a1-specific antisense oligos or anti-\nCYP26A1 antibodies were injected into the uterus on day \n3 of pregnancy (Han et al . 2010). As described previously, \nthe RA pathway is inhibited during the late secretory \nphase by endogenous expression of Cyp26a1. RA can \ninhibit matrix metalloproteases ( Bruner-Tran et al . 2002, \nOsteen et al . 2003), thus, CYP26A1-mediated degradation \nof RA may facilitate blastocyst implantation (Osteen et al . \n2003).\nPharmacological concentrations of RA are embryotoxic \nat the early postimplantation stage of development \n(Huang et  al . 2001 ). This observation, along with the \nwell-characterized functions played by CXs in embryonic \nimplantation and development, suggests a possible link \nbetween known teratogenic effects of RA (Ross et al . 2000) \nand the possibility that RA at such concentrations may \nreduce the effective trophoblast invasive capacity through \nincreased GJIC because CX43 expression and GJIC are \ndramatically reduced during the implantation window \n(Granot et al . 2000) potentially facilitating trophectoderm \ninvasion into the endometrial stroma.\nOther studies established the importance of \nendometrial gland secretions, such as leukemia inhibitory \nfactor (LIF), for endometrial receptivity and blastocyst \nimplantation. LIF binds to its receptor LIFR present in \nluminal epithelia and activates downstream signaling \nvia STAT3 (Niwa et al . 1998). Consequently, LIF induces \nthe expression of luminal epithelia-enriched genes, \nincluding HB-EGF1, IGFBP3 and IRG, which are associated \nwith uterine receptivity ( Kimber 2005). Lif KO mice are \ninfertile because of the failure of blastocyst attachment \nto the uterine luminal epithelium. Excess RA (10 µM) can \nsignificantly inhibit the expression of the Lif, Hb-egf and \nCsf1 in endometrial epithelial cells isolated on day 4.5 of \npregnancy (Ma et al . 2012) (Table 2 ).\nThese data suggest that successful implantation \nduring late secretory phase requires lower RA levels in the \nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR180\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\nluminal epithelia than what occurs in the proliferative \nphase, and excess RA might negatively affect stromal \ndecidualization, endometrial receptivity and blastocyst \nimplantation. CYP26A1-mediated degradation of RA is a \nhallmark of the implantation phase.\nCollectively, the endometrial retinoid pathway is \ndistinctly regulated by synthesis catalyzed by ALDHs and \ncatabolism catalyzed by CYP26A1 at different phases and \nin different compartments of the endometrium, which \nare mainly controlled by estradiol and progesterone. The \nretinoid pathway plays crucial roles in endometrial epithelial \ndifferentiation and proliferation, neovascularization and \nGJIC and negatively regulates stromal decidualization and \nblastocyst implantation ( Fig. 3 ).\nRetinoid pathway and endometriosis\nEndometriosis is a nonmalignant, but potentially \nmetastatic, gynecological condition, which is estrogen \ndependent and defined by the presence of hormonally \nresponsive, ectopic implants of endometrial mucosa \ndispersed in extrauterine locations ( Giudice & Kao 2004 , \nKennedy et al . 2005). Approximately 10% of all women \nand up to 30%–50% of symptomatic premenopausal \nwomen are affected and commonly suffer pelvic \npain and/or infertility ( Nnoaham et  al . 2011 , Stilley \net  al . 2012 ). Classical and neoclassical concepts of \nendometriosis etiology were reviewed comprehensively \nelsewhere ( Bulun 2009 , Taylor 2010, Burney & Giudice \n2012, Bulun et  al . 2015 , Taylor et  al . 2015 ) and will \nnot be reiterated thoroughly in this review. Although \nthe theories of endometriosis histogenesis remain \ncontroversial, recent findings suggest that defective \nepigenetic landscape possibly associated with deficient \ndifferentiation of endometrial tissue stem cells is a \ncentral mechanism responsible for the cellular origins of \nendometriosis ( Bulun et  al . 2015 ). Meanwhile, retinoid \npathway is fundamentally flawed in endometriotic tissues \nand even systemically in women with endometriosis \n(Pavone et al . 2010, 2011, 2017, Pierzchalski et al . 2014, \nTaylor  et al . 2015 ).\nStudies from the group of Bulun showed altered \nexpression of several genes involved in retinol uptake, \nmetabolism and action in cells from patients with \nendometriosis ( Pavone et  al . 2010 , 2011, 2017). \nEndometriotic stromal cells overall had decreased CRABP2 \nand CRBP1 expression and increased CYP26B1 expression \n(Table 4 ), the latter resulting in the elimination of RA from \ncells. These results are consistent with decreased retinoid \nuptake, metabolism and action within endometriotic \nlesions (Pavone et  al. 2011). ALDH1A2 expression levels \nwere significantly reduced in endometriotic tissue and \nstromal cells ( Table  4 ), resulting in reduced RA levels. \nPierzchalski et  al.  (2014)  directly quantified RA levels \nand biosynthesis from retinol in endometrial stromal \ncells, which were derived from corresponding eutopic \nand ectopic biopsies; retinol uptake and RA production \npredominantly occur in these stromal cells ( Vermot et al . \n2000, Pavone et  al. 2011, Yamagata et  al. 2014) (Fig.  1). \nThe studies confirmed impaired RA biosynthesis in \nendometriotic implants. A major defect was the reduced \nexpression of CRBP1, a retinol carrier protein serving as \nthe preferred substrate for retinol dehydrogenase enzymes \nand the rate-limiting factor in RA biosynthesis ( Napoli \n2012). Moreover, STRA6, which mediates retinol uptake, \nshowed an abnormally low expression and high levels of \nDNA methylation in endometriotic stromal cells ( Pavone \net al . 2011, Yamagata et al . 2015) (Table 4 ). Thus, reduced \nSTRA6, CRBP1 and ALDH1A2 expression levels result in \na significantly less efficient conversion of retinol to RA \nin stromal cells. In addition,  RAR α expression levels are \nstrikingly low in tissues and stromal cells of endometriosis \n(Pavone et al . 2011) (Table 4). Transcriptional activation via \nthe RA-CRABP2-RAR pathway can trigger cell cycle arrest \n(Donato et  al . 2007 ) and apoptosis ( Altucci et  al . 2001 , \nKitareewan et al . 2002, Donato et al . 2005) and frequently \nleads to the inhibition of cell proliferation. Thus, reduced \nRA-CRABP2-RAR signaling can cause endometriotic cells to \nescape apoptosis and contribute to the survival of ectopic \ncells (Nasu et al . 2009, Pavone et al . 2010). These studies \nsuggested that flaws in RA production and degradation \nmight play a role in the pathogenesis of endometriosis.\nTable 4 Changes in genes involved in retinoid uptake, \nmetabolism and signaling in endometriosis.\nGenes Changes Cell type References\nCRBP1 ↓ Stromal cells Pavone et al. (2011, \n2017)\nCRABP2 ↓ Stromal cells Pavone et al. (2010, \n2011, 2017)\nALDH1A2 ↓ Stromal cells Pavone et al. (2011)\nSTRA6 ↓ Stromal cells Pavone et al. (2010, \n2011), Yamagata et al. \n(2015)\nRARα ↓ Stromal cells Pavone et al. (2011)\nRXRα ↓ Stromal cells Pavone et al. (2011)\nCYP26B1 ↑ Stromal cells Pavone et al. (2011, \n2017)\n↓, reduced; ↑, increased.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR181\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\nEstrogen plays a critical role in the establishment and \nmaintenance of endometriosis (Osteen et al . 2005, Bulun \n2009, Bulun et  al. 2015). 17β-hydroxysteroid dehydrogenase \ntype 2 (HSD17B2) catalyzes the conversion of estradiol \nto estrone, a much less biologically potent estrogen, and \nplays a crucial role in local estradiol inactivation in the \nendometrium (Cheng et al . 2007). HSD17B2 is present in \nnormal endometrial glandular cells but is lacking in the \nendometrium of women with endometriosis ( Stewart \n1994, Giudice et al . 2002). Pavone et al . (2017) incubated \nepithelial cells with human serum RBP4 for 48 h and found \nthat HSD17B2 expression was significantly increased in a \ndose-dependent manner. In serum, retinol is bound by \nRBP4 in the form of retinol-RBP4 complex (holo-RBP4), \nwhich then binds to transthyretin (TTR) and forms a \nternary complex ( D’Ambrosio  et  al . 2011 ). Binding of \nholo-RBP4 to TTR prevents the loss of the RBP4 from the \ncirculation by filtration via the renal glomeruli, as apo-\nRBP4 cannot be bound by TTR and is lost in the urine. \nSince the human serum RBP4 used in the study of Pavone \net  al . (2017)  may contain significant amounts of holo-\nRBP4, the increased HSD17B2 expression might be caused \nby retinol from holo-RBP4. This hypothesis was supported \nby another study which demonstrated that RA stimulates \nthe assembly of a multimeric complex composed of RARα/\nRXRα tethered to transcription factors SP1 and SP3 on the \nHSD17B2 promoter where it induces HSD17B2. The RA \nantagonist ANG abolishes RA-induced HSD17B2 expression \nin endometrial cells ( Cheng  et  al . 2008 , Yamagata et  al . \n2015). Thus, RA appears to be one of the critical paracrine \nfactors that stimulate the production of HSD17B2 in \nneighboring epithelial cells and an important mechanism \nfor local estradiol inactivation in the endometrium \n(Table 2 ). As previously mentioned, as the RA pathway is \nfundamentally flawed in endometriotic tissues ( Pavone \net al . 2010), this provides a plausible explanation for the \naberrant HSD17B2 expression and the high local estradiol \nconcentrations in endometriosis (Fig. 4 ).\nAs previously mentioned, CX43 is predominantly \nexpressed in endometrial stromal cells ( Jahn et al . 1995, \nWinterhager et al . 2009) and necessary for GJIC that allow \nthe stroma to serve as an organized tissue. Regidor et al . \n(1997) showed that CX43 levels were reduced in human \nendometriosis lesions and this finding was confirmed by \nYu et  al . (2014 b). They reported nearly exclusive CX43 \nimmunostaining in the stromal compartment of normal \nbiopsies, with reduced immunostaining and redistribution \nto scattered epithelia in the eutopic endometria of women \nwith endometriosis. Moreover, stromal cells isolated from \ncases of endometriosis exhibited a reduction of ~45% in \nGJIC, confirmed at the levels of CX43 mRNA and protein \nexpression and also functionally by lower Lucifer Yellow \ndiffusion ( Yu et  al . 2014 b). As previously mentioned, \nRA can stimulate CX43 expression and GJIC in stromal \ncells ( Tanmahasamut & Sidell 2005 , Wu et  al . 2013 ). \nThus, flawed retinoid action might cause decreased CX43 \nexpression and GJIC, reducing decidualization capacity of \nstromal cells in endometriosis, which could contribute to \nthe development or progression of endometriosis lesions \nand to the subfertile uterine phenotype associated with \nthe syndrome.\nTGF-β1, a member of transforming growth factor- β \n(TGF-β) superfamily, has been supposed to play an extensive \nrole in the onset and development of endometriosis, such \nFigure 4\nSchematic representation of aberrant retinoid signaling in endometriosis. \nIn stromal cells of endometriosis, reduced STRA6, CRBP1 and ALDH1A2 \nexpression levels result in a significantly less efficient conversion of \nretinol to RA. Meanwhile, increased CYP26A1 expression promotes RA \ndegradation. Thus, decreased RA levels along with reduced RARα and \nCRABP2 expression result in a reduced RA-RAR signaling, which results in \nreduced Cx43 expression and GJIC in stromal cells. Meanwhile, reduced \nRA levels result in lower HSD17B2 production and high local \nconcentrations of estradiol (E2) in epithelial cells of endometriosis. The \nreduced RA signaling and increased local E2 activity could enhance cell \nproliferation, invasiveness and impede apoptosis in endometriosis. A full \ncolour version of this figure is available at https://doi.org/10.1530/\nJOE-17-0544.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR182\nRetinoids and endometriumY Jiang et al.236:3\nJournal of \nEndocrinology\nas preventing apoptosis during transit to the peritoneal \ncavity, promoting adhesion to peritoneum and invasion \nof endometriosis cells (Omwandho et al . 2010). With the \nexception of one study (Hao et al . 2000), two other studies \nreported that subjects with endometriosis exhibit higher \nlevels of TGF- β1 in peritoneal fluid ( Oosterlynck et  al . \n1994, Ku¨pker  et  al . 1998). Interestingly, it was reported \nthat RA could inhibit the TGF-β1 signaling pathway in the \nendometrial cells and many other cell types ( Frenz & Liu \n2000, Delgadillo et al. 2014, Hu et al. 2016). Althoughfurther \nstudies are needed, it can be speculated that RA might \nsuppress the development of endometriosis implants partly \nthrough repressing the TGF-β1 signaling pathway (Fig. 5 ).\nThese data suggest two possible scenarios to consider \nthe theories of the histogenesis of endometriosis associated \nwith the aberrant retinoid pathway in ectopically growing \nendometrial cells. On the one hand, defects in RA signaling \ncan result in high local concentrations of estradiol in \nendometriosis lesions due to deficient oxidation and \ninactivation of estradiol. On the other hand, reduced RA \nsignaling, along with increased estradiol effects, could \nenhance cell proliferation and invasiveness and impede \napoptosis in endometriosis ( Fig.  4 ). With respect to \neutopic endometrial function in endometriosis, impaired \nRA signaling can be an attributed to dysfunctional \nstromal differentiation, leading to the reduced capacity \nfor decidualization reported in these cases ( Klemmt et al . \n2006, Aghajanova et al . 2009, Lessey et al . 2013).\nIn conclusion, the precisely controlled retinoid \nsignaling may play a critical role in a number of critical \nendometrial physiological events. In addition, the altered \nRA pathway may be a leading cause for the histogenesis \nof endometriosis.\nPerspectives for future studies\nRBP4, acting as the primary systemic and intercellular \ntransporter of retinol, plays a key role in cellular retinol \ninflux, efflux and exchange ( Kawaguchi et  al . 2015 ). \nPavone et  al . (2017)  observed that RBP4 secretion \nincreases during the decidualization of human \nendometrial stromal cells. Immunoreactivity for RBP4 is \nconsistently higher near the embryo implantation site \ncompared with non-implantation sites in the baboon \nendometrium ( Fazleabas et al . 1994). These data suggest \na potential role of RBP4 production and secretion in \ndecidualization and/or implantation, but still require \nfurther investigation. Of great interest is that complete \ndeletion of Aldh genes in mice results in prenatal \nlethality, precluding investigation of their roles in \npostnatal organogenesis. The use of tissue-selective and \nconditional gene targeting approaches is necessary to \nbetter understand the role of these enzymes during the \novarian cycle and gestation. As previously mentioned, \nexcess RA concentration is harmful to decidualization \nand implantation. Thus, actual retinoid concentrations \nin the endometrium, as have been performed in some \nlimited studies ( Pierzchalski et  al . 2014 ), should be \nmeasured in future studies.\nAccumulating evidence supports that treatment \nmodalities that target the retinoid pathway may have \ntherapeutic utility ( Sokalska et  al . 2013 ). RA treatment \nreduced cytokine concentrations and the number and size \nof lesions (Wieser et al . 2012). Thus, RA has the potential \nto suppress the development of endometriotic implants \nand agents that target the RA-shuttling system may be \nuseful therapeutic targets in the future, bypassing the \ntoxicity and teratogenicity encountered with RA analogs \n(Fig. 5 ). We propose that adjuvant or alternative medical \ntherapies should be developed on the basis of these \nconcepts. Their pharmacological actions and anticipated \nlow side-effect profiles are predicted to be able to provide \nwomen with endometriosis with more treatment options \nfor the long-term management of chronic and debilitating \ngynecologic diseases.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nFigure 5\nPotential therapeutic mechanism of RA for \nendometriosis. Activation of the RA-RAR pathway \ncan promote HSD17B2 production, which can \nstimulate the catabolism of E2 and inhibit TGF-β1 \nproduction. These actions of the RA-RAR pathway \nimply its potential to suppress the development \nof endometriosis. A full colour version of this \nfigure is available at https://doi.org/10.1530/\nJOE-17-0544.\nDownloaded from Bioscientifica.com at 06/13/2026 08:18:42AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-17-0544\nhttp://joe.endocrinology-journals.org © 2018 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR183\nReview\nY Jiang et al. Retinoids and endometrium\n236:3\nJournal of \nEndocrinology\nFunding\nThis work was supported by the National Natural Science Foundation of \nChina (31372308 to X Z, 31772596 to X Z, 31672417 to C L and 31301969  \nto L C) and by the Eunice Kennedy Shriver National Institute of Child Health \nand Human Development (USA) as part of the Cooperative Research \nPartnerships to Promote Workforce Diversity in the Reproductive Sciences \n(U01 HD66439 to R N T).\nReferences\nAghajanova L, Hamilton A, Kwintkiewicz J, Vo KC & Giudice LC 2009 \nSteroidogenic enzyme and key decidualization marker dysregulation \nin endometrial stromal cells from women with versus without \nendometriosis. Biology of Reproduction 80 105–114. (https://doi.\norg/10.1095/biolreprod.108.070300)\nAl Tanoury Z, Piskunov A & Rochette-Egly C 2013 Vitamin A and retinoid \nsignaling: genomic and nongenomic effects. Journal of Lipid Research \n54 1761–1775. 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