{"paper_id":"afe89f2b-6c0c-4a3d-b97d-6c5acd8fe153","body_text":"Creative Commons Attribution-Non Commercial 4.0  ●  August 2022  ●  Reproductive Health\n51\nProgesterone Resistance in Endometriosis\nAbstract\nEndometriosis is characterised by the presence of endometrium-like tissue on the \npelvis and other organs. Progesterone resistance due to suppressed progesterone \nreceptor (PGR) expression and action is a general feature of endometriosis and is \na cause of endometriosis-associated chronic pelvic pain, infertility, inflammatory \ndisorders, and cancer. It appears that progesterone receptor polymorphisms may \nnot be associated with the susceptibility to endometriosis. On the other hand, PGR \nexpression and activity in target cells is significantly dysregulated in both eutopic \nand ectopic tissues compared with control endometrium. However, the underlying \nepigenetic mechanisms for PGR suppression in the eutopic tissue are different \nfrom ectopic tissue. The aim of this paper was to present an overview of different \naspects of progesterone resistance and its application in endometriosis. Finally, \nthis article also presents a few important, unmet questions related to the failure of \nprogesterone treatment in alleviating clinical conditions in endometriosis. \nAuthors: Jeevitha Poorasamy, Jayasree Sengupta,  \nAsmita Patil, *Debabrata Ghosh\nDepartment of Physiology, All India Institute  \nof Medical Sciences, New Delhi, India\n*Correspondence to debabrata.ghosh1@gmail.com\nDisclosure: The authors have declared no conflicts of interest.\nReceived: 29.03.22\nAccepted: 19.05.22\nKeywords: Endometriosis, epigenesis, infertility, pelvic pain, progesterone \nreceptor (PGR), progesterone resistance.\nCitation: \nEMJ Repro Health. 2022;8[1]:51-63.  \nDOI/10.33590/emjreprohealth/22-00109.  \nhttps://doi.org/10.33590/emjreprohealth/22-00109.\nKey Points\n1. Endometriosis affects nearly 10% of females of reproductive age; progestin treatment fails in a large \nnumber of these patients, likely due to progesterone resistance.\n2. Progesterone resistance may be due to suppressed progesterone receptor expression and action \nand is a cause of endometriosis-associated chronic pelvic pain, infertility, inflammatory disorders, and \ncancer.\n3. There is an urgent need for deeper understanding of the cellular and molecular mechanisms of \nprogesterone resistance in endometriosis, for both ectopic and eutopic tissues, to underpin novel \napproaches to treatment.\nReview\n\n52\nReproductive Health  ●  August 2022  ●  Creative Commons Attribution-Non Commercial 4.0\nINTRODUCTION \nGrowth of endometrial tissue outside the uterus, \nfrequently but not exclusively, in the pelvic \nstructures gives rise to endometriotic lesions in \nthe peritoneum (peritoneal endometriosis), the \novary (ovarian endometriosis or endometrioma), \nand the deep pelvis (deep infiltrating \nendometriosis), and infrequently in the distant \norgans.1 According to Sampson’s theory, deposits \nof viable endometrial cells following their reflux \ninto the peritoneal space via the fallopian tubes \nduring menstruation may adhere and grow, \nand give rise to endometriosis.2 In an elegant \nreview, Redwine3 challenged this theory and \ndemonstrated, by analysing a large number of \nparameters, that endometriosis tissue is primarily \nreflected dissimilarity than similarity with eutopic \nendometrium in the uterus, including inadequate \nsecretory differentiation in endometriotic cells \nunder progesterone dominance during the  \nluteal phase.  \nNisolle and Donnez4 speculated that inadequate \nsecretory maturation in the endometriosis \nmight cause from the reduction in progesterone \nreceptor (PGR). Zeitoun et al.5 and Attia \net al.6 observed that 17-β-hydroxysteroid \ndehydrogenase type 2 (17β-HSD2), the activity \nof which transforms oestradiol to less potent \noestrogen (oestrone) and is stimulated by \nprogesterone in endometrial glands, was \nsignificantly reduced in endometriotic tissue \nduring the luteal phase, along with markedly \nrepressed levels of immunoprecipitable PGR \nthroughout the menstrual cycle. \nThe fact that progestin treatment fails to \nregress endometriosis in three out of 10 females \nis also indicative of inadequate machinery \nof progesterone action in the endometriotic \ntissue.7,8 These observations were suggestive of \nthe absence of certain responses to  \nprogesterone action. \nTaking these observations together, a theory \nof ‘progesterone resistance’ as the mediator of \npathogenesis of endometriosis was forwarded \nin the 2000s. Since then, though more intensely \nin the last decade, the theory has been under \nscrutiny.8-12 An overview of this theory and \nits application in explaining the pathogenesis \nof endometriosis and its management will be \npresented in this paper.\nPROGESTERONE RECEPTOR \nProgesterone is a steroid hormone primarily \nsynthesised by the ovaries and adrenal glands, \nand also by the placenta during pregnancy. \nProgesterone, although quintessentially the \n‘pregnancy hormone’ , also plays an important \nrole in several non-reproductive tissues such \nas the breast, heart and vascular system, \nbrain, and bones.13 The physiological actions of \nprogesterone in target cells are mediated by its \nbinding to PGRs: classical and non-classical. \nTypically, classical PGR regulates the expression \nof progesterone responding genes, which \nresult in slowly emerging, long lasting cellular \nresponses. On the other hand, progesterone \nbinding to non-classical PGR activates secondary \nmessengers and signal transduction pathways \nand mediates rapid responses. A detailed \ndiscussion on the physiology of different types \nof PGR is beyond the scope of the present paper; \nhowever, the authors present a synopsis on the \ntopic in the following section. Interested readers \nmay be referred to the comprehensive review \narticles that covered different aspects  \nof PGR in mammalian cells and specifically  \nin endometrium.11,14-19\nClassical Progesterone Receptors \nThere are two main isoforms of classical PGR: \nPGR-A (94 kDa) and PGR-B (120 kDa). Both are \ntranscribed from the same gene, but by two \ndifferent promoters. As schematically presented \nin Figures 1 and 2, these two isoforms are very \nsimilar except that PGR-A lacks 164 amino acids \nthat are present at the N-terminus of PGR-B. \nUnbound PGR in cytoplasm are complexed with \nchaperone proteins.14-19 Several lines of evidence \nsuggests that PGR-A is functionally distinct from \nPGR-B, and thus tissue-specific distribution \npatterns of PGR-A and PGR-B result in the \nobserved diversity of progesterone- \nmediated actions. \nGenerally, PGR-B is the positive regulator \nof the effects of progesterone, while PGR-A \nserve to antagonise the effects of PGR-B.14 \nWhen progesterone binds to the ligand-binding \ndomain of PGR, the receptor initiates a series \nof conformational changes, and it is released \nfrom the chaperone proteins to finally enter \ninto the nucleus. In the nucleus, PGR dimerises \nto form homodimers (AA, BB) or heterodimers \nReview\n\nCreative Commons Attribution-Non Commercial 4.0  ●  August 2022  ●  Reproductive Health\n53\n(AB), and binds to the progesterone response \nelement sequence in the target gene.14-19 A third \nvariant of PGR, PGR-C isoform (60 kDa), has \nalso been described in humans (Figures 1 and 2). \nPGR-C also can form heterodimers with PGR-A \nand PGR-B and regulates their transcriptional \nactivity.20 Such diverse possibilities of \ndimerisation of PGR potentially gives rise to \na wide variety of physiological responses. \nThe binding of PGR dimer to progesterone \nresponse elements follows their recruitment to \ncoregulators (coactivators or corepressors) and \nregulation of the subsequent PGR-mediated \ntarget gene expression in an isoform- \nspecific manner.14,19 \nFigure 3 shows a schema of canonical \nmechanism of PGR action. PGR isoforms interact \nwith one another and mutually regulate their \nown activity. For example, PGR-A inhibits PGR-B \naction by its inhibitory domain and, thereby, \nPGR-A decreases the effects of progesterone \non its target cells.14,19 Additionally, tissue-specific \ncoregulator expression along with subnuclear \nlocalisation of PGR and coregulator  \nassociation may mediate tissue-specific \nprogesterone action.14,19,23\nNon-classical Progesterone Receptors \nNon-classical PGRs are usually located on the \ncell surface as single transmembrane receptors. \nThese receptors belong to G protein-coupled \nreceptor superfamily and are associated with \ntyrosine kinase activity. Non-classical PGRs are \nof two types: membrane progestin receptors \n(mPR) family, also named the progestin and \nadipoQ receptor (PAQR), and the progesterone \nPGR-B (120 kDa), but not PGR-A (94 kDa), includes 164 additional amino acids in the NTD (shown as BUS), \nwhere the AF3 domain and multiple phosphorylation sites are located. The NTD also contains an activa-\ntion factor domain (AF1), which is common for PGR-B and PGR-A. The protein tertiary structure results in a \nfolding at the H region between the DBD and LBD. The green bars in the DBD represent zinc-finger motifs. \nPost-translational phosphorylation (shown as green ellipses), acetylation (shown as violet triangle), and \nSUMOylation (shown as green hexagon) can occur basally or in response to ligand binding and affect PGR \ntranscriptional activity. The numbering reflects amino acid residue positions.\nAF1: first activation factor; AF2: second activation factor; AF3; third activation factor; BUS: B-upstream seg-\nment; DBD: DNA-binding domain; LBD: ligand-binding domain; NTD: N-terminal domain; PGR:  \nprogesterone receptor.\nFigure 1: Three isoforms of classical progesterone receptors. \nReview\n\n54\nReproductive Health  ●  August 2022  ●  Creative Commons Attribution-Non Commercial 4.0\nreceptor membrane component (PGRMC) \nfamily, both having several subtypes.8,11,16,19,24 \nThere is evidence to suggest that both types \nof non-classical PGRs may interact to mediate \ntheir actions in target cells. The physiological \nsignificance of non-classical PGRs in the uterus \nis not clear. However, as discussed in the \nfollowing section, these receptors are associated \nwith the menstrual phase specific functions of \nuterine cells.8  \nProgesterone Receptors in \nEndometrium \nBoth classical and non-classical PGRs exhibit \ndifferential expression depending on endometrial \ncell type, and the phase of the menstrual \ncycle (Figure 4). Both PGR-A and PGR-B \nare expressed in the endometrial epithelium \nduring early to mid-luteal phase, seemingly \nin preparation of embryo implantation.18,19 The \ninhibitory effect of PGR-A on the expression of \nPGR-B causes negative regulation of the action \nof PGR-B, and thereby promotes hyperplasia \nand inflammation in this tissue.18,19 During \nimplantation, however, the expression level \nof PGR-A drops, while that of PGR-B remains \nconstant to support the secretory function of \nglands of endometrium functionalis. On the \nother hand, PGR-A is the dominant isoform in \nendometrial stromal cells throughout the luteal \nphase and provides support to decidualisation, \nwhich is integral to the implantation process.16-19 \nIn fact, very low expression of both isoforms \nin endometrial cells may result in unexplained \ninfertility and implantation failure. PGR knockout \nexperiments in mouse studies demonstrated \nthat the expression of PGR-A, but not of PGR-B, \nis obligatory for successful implantation and \nestablishment of pregnancy.25 On the other hand, \nthe overexpression of PGR-A results in uterine \nenlargement and endometrial hyperplasia.8,10,18 \nThus, the ratio of PGR-A-to-PGR-B appears \ncritical for the normal response of  \nendometrium to progesterone.26\nAmong non-classical PGRs in humans, transcript \nlevels of PGRMCs, mPRα, mPRγ, and mPRε \nfluctuate depending on the menstrual cycle \nphase. For example, levels of messenger RNAs \n(mRNA) for PGRMC1, mPRγ, and mPRε are \nupregulated during the proliferative phase and \nprogressively decrease during the secretory \nphase, whereas mRNAs for mPRα and PGRMC2 \nare higher in the secretory phase along the \nincreasing levels of luteal progesterone.8,16,19,24 On \nthe other hand, the levels of mPRβ, which are \nrelatively higher in the human endometrium than \nthat of mPRα, do not change significantly during \nthe menstrual cycle; however, its expression is \ncritical on Days 10–14 of the human menstrual \ncycle, as revealed in patients with a history of \nrecurrent spontaneous abortion.16,19 \nThe nuclear PGR gene is composed of eight exons with 3100-bp coding regions and 5’- and 3’-untranslated \nregions. PGR-B and PGR-A isoforms are transcribed from two alternate transcription initiation sites and are \nidentical to amino acids 165–993. PGR-C (60 kDa) isoform results from an in-frame initiation of translation \nand lacks exon 1.\nBUS: B-upstream segment; DBD: DNA-binding domain; LBD: ligand-binding domain; PGR:  \nprogesterone receptor.\nFigure 2: Schematic representation of genomic configuration of three classical progesterone receptor \nisoforms and splice variants. \nReview\n\nCreative Commons Attribution-Non Commercial 4.0  ●  August 2022  ●  Reproductive Health\n55\nAs seen in Figure 4, PGRMC1 and PGRMC2 \nshow inverse expression patterns during the \nmenstrual cycle. PGRMC1 displays regulatory \naction on PGRMC2. PGRMC1 is involved in cell \nproliferation in the endometrium during the \nproliferative phase of the menstrual cycle.16,19 On \nthe other hand, PGRMC2 inhibits cell proliferation \nand supports endometrial differentiation during \nthe secretory phase of the menstrual cycle.16,19,24 \nThus, the reported inverse profiles of PGRMC1 \nand PGRMC2 in the glandular and stromal \ncompartments of human endometrium during \nthe menstrual cycle appears important for \nendometrial growth and maturation. Several lines \nof evidence indeed indicate that both PGRMC1 \nand PGRMC2, and their expression ratio in \nendometrial epithelial and stromal components, \nare critical for endometrial preparation for \nsuccessful pregnancy.16,24 \nPHYSIOLOGICAL BASIS OF \nPROGESTERONE RESISTANCE  \nIn a case report, Keller et al.27 reported on \na 23-year-old female with initial complaint \nof infertility, who demonstrated inadequate \nendometrial maturation during luteal phase \nconsistent with inadequate corpus luteum \nsyndrome; however, she had a normal serum \npattern of progesterone, oestradiol, follicle-\nstimulating hormone, luteinising hormone, \nand their cytosol-binding proteins. Exogenous \nprogesterone did not correct the abnormality. \nFurther investigation revealed inadequate \nmaturation of her endometrium that caused from \na markedly reduced number PGR in the target \ncells.27 Thus, it appeared that the condition \nof 'pseudocorpus luteum insufficiency' could \nhave occurred due to progesterone resistance \nat the receptor level in the target cells of \nendometrium.28 Similar defect had been reported \nin a subgroup of females with infertility.29 \nLigand-free PGRs are present as inactive complexes associated with HSPs and chaperone proteins (p23 \nand p59). When progestin binds to the PGR, it undergoes conformational changes along with dissociation \nof HSPs and chaperone proteins (p23 and p59). PGRs then undergo dimerisation and bind to the HRE in the \ntarget DNA. Ligand-dependent conformational changes allow for the recruitment of cofactors and other \nGTFs to the promoter, producing a transcriptionally active complex that can direct gene transcription. \nAdapted from Mani S, Portillo W.21 and Hill KK et al.22\nGTF: general transcription factors; HRE: hormone response element; HSP: heat shock protein: P4: progester-\none; PGR: progesterone receptor; PRE: progesterone response element.\nFigure 3: A simplified scheme of the mechanism of progesterone receptor activation.\nReview\n\n56\nReproductive Health  ●  August 2022  ●  Creative Commons Attribution-Non Commercial 4.0\nGene polymorphisms and epigenetic \nmodifications to PGR may, theoretically, cause \nsuch progesterone resistance. Furthermore, \nanomalies in down-stream signalling elements, \ntarget genes, and regulator modules that are \ndirectly and indirectly linked to progesterone \nactions may cause functional progesterone \nresistance. Both types of progesterone \nresistance may be constitutively present in \nthe target tissue or may be acquired by the \ntarget cells.9,10,30,31 In the following sections, the \nauthors discuss how both types of progesterone \nresistance are associated with endometriosis. \nPROGESTERONE RESISTANCE IN \nENDOMETRIOSIS \nEctopic Tissue \nThere is substantial evidence to suggest that \nprogesterone resistance is a general feature \nof endometriotic lesion. Table 1 lists some of \nthe supporting studies. As mentioned above, \nprogesterone treatment could not induce \nthe conversion of oestradiol to oestrone in \nectopic tissue.32 The enzyme 17β-HSD2, which \nis responsible for catalysing the reaction, is \nupregulated by progesterone in secretory \nepithelial cells of normal endometrium, but not \nby ectopic cells, providing the first-line evidence \nof progesterone resistance in endometriosis.5 In \nfact, PGR concentrations, for both PGR-A and \nPGR-B, in endometriosis tissue are generally \nrepressed.6,33,34,44 Thus, it appears that attenuated \nPGR may result in altered gene transcription \nin ectopic tissue, even when progesterone \nconcentration in circulation is normal. \nSeveral large-scale gene expression studies \nrevealed significant differences between \nectopic and matching eutopic tissue. Many of \nthe genes with differential expression were \nindeed progesterone target genes.37,38,42,43,45 In \nthis regard, it is notable that there are reports \nof increased PGR expression in endometrioma, \nwith a higher or unchanged PGR-B expression \nin endometrioma compared with normal \nendometrium.36,41 Interestingly, PGR expression \nwas reportedly lower than in endometrium in \nprimary endometriotic lesions, while in recurrent \nlesions there was no difference in PGR expression \nas compared with eutopic endometrium.46 \nIn another study, lower PGR expression was \nobserved in stromal cells of ectopic lesions \ncompared with eutopic tissue, while epithelial \ncells of ectopic lesion showed higher PGR \nexpression in late secretory phase.35\nMarked expression of PGR-A and PGRR-B in the LP and at MS is notable. PGRMC1 and PGRMC2 show sub-\ntle differential expression patterns during the menstrual cycle. \nAdapted from Reis FM et al.8 \nEP: early proliferative phase; ES: early secretory phase; LP: late proliferative phase; LS: late secretory phase; \nM: menstrual phase; MP: mid-proliferative phase; MS: mid-secretory phase; PGR: progesterone receptor; \nPGRMC: progesterone receptor membrane component.\nFigure 4: Expression pattern of classical progesterone receptor-A and progesterone receptor-B and mem-\nbrane receptors progesterone receptor membrane component 1 and progesterone receptor membrane \ncomponent 2 in glandular (shown as “Gland”) and stromal compartment (shown as “Stroma”) of human \nendometrium in a typical menstrual cycle. \nReview\n\nCreative Commons Attribution-Non Commercial 4.0  ●  August 2022  ●  Reproductive Health\n57\nEutopic Tissue \nIt is evident from the above discussion that \nectopic tissue of females with endometriosis \ndisplay suppressed PGR expression. The \nquestion whether a similar PGR suppression \nexists in the eutopic endometrium of females \nwith endometriosis is rather unsettled. Table 2 \nprovides a list of studies and the summary of \nresults therein reflecting inconsistencies in  \nthis regard. \nIn a large-scale gene expression study, a higher \nclustering between proliferative and secretory \nphase samples from eutopic endometrial \nbiopsies as compared with normal endometrium \nwas observed, and it was associated with a \nsubstantial number of PGR target genes being \naffected.48 Collectively, these results were \nsuggestive of inadequate progesterone-mediated \ntransition of late proliferative to the early \nsecretory phase in females with endometriosis. \nFurthermore, there are studies indicating a \ndecrease in the PGR-B:PGR-A ratio along \nwith relatively high PGR-A expression in \neutopic endometrium compared with normal \nAdapted from Yang S et al.67\nDKK1: Dickkopf-related protein 1; FOXO1: Forkhead box protein O1; MMP: matrix metalloproteinase; NF-κB: \nnuclear factor κ-light-chain-enhancer of activated B cells; PAEP: human placental protein-14; PGR: proges-\nterone receptor.\nFigure 5: Progesterone mediated networks of regulatory pathways that promote (shown as the green ar-\nrow) cell cycle arrest, apoptosis, and differentiation, and inhibit (shown as the red blocked arrow) inflam-\nmation and invasion. \nReview\n\n58\nReproductive Health  ●  August 2022  ●  Creative Commons Attribution-Non Commercial 4.0\nName with year Major relevant observation\nVierikko et al.32 Lack of induction of 17β-HSD activity by progesterone, medroxy-progesterone acetate, \nor danazol was observed in endometriosis tissue along with lower concentration of PGR.\nPrentice et al.33 Quantitatively lower immunopositive PGR expression was observed in endometriotic \ntissue compared to paired eutopic endometrium.\nBergqvist et al.34 Significantly lower expression of immunopositive PGR was observed in epithelial cells of \novarian endometriosis than in endometrial epithelial cells, but not in stromal cells.\nJones et al.35 Lower PGR expression in stromal cells of ectopic lesions compared with eutopic tissue, \nwhile epithelial cells of ectopic lesion showed higher PGR expression only in the late \nsecretory phase. \nZeitoun et al.5 Deficient 17β-HSD2 expression, which is regulated by progesterone, was observed in \nendometriosis.\nMisao et al.36 Dominant expression of PGR-B mRNA in ovarian endometriosis.\nAttia et al.6 PGR-A but not PGR-B was expressed in endometriosis.\nMatsuzaki et al.37,38 Significantly higher levels of PGR regulated 17β-HSD2 mRNA in epithelia of ectopic \nlesions of ovarian endometriosis compared with matched eutopic endometrium in \nsecretory phase of menstrual cycle of ovarian endometriosis. No such difference was \nobserved in deep endometriosis. In fact, 17β-HSD2 expression was not detected in \neither epithelial or stromal cells of 50% ectopic samples.\nWu et al.39 Large-scale transcriptional characterisation of differences between eutopic and ectopic \nendometrium revealed 904 differentially expressed genes contributing to 79 pathways, \nwith over 100 genes with known functions, including PGR dependent signalling systems \n(Wnt and MAPK signalling).\nBukulmez et al.40 Increased expression of PGR-C mRNA relative to PGR-A and PGR-B mRNA was observed \nin ovarian endometriosis compared with eutopic and control endometrium. The PGR-A \nprotein was barely detectable in endometriomas. The significance of the observations \nlies in the fact that PGR-A and PGR-B serve an anti-inflammatory role in the uterus by \nantagonising NF-κB activation and COX-2 expression, while PGR-C expression, which \nantagonises PGR-B, is associated with inflammation.\nSmuc et al.41 Expression analysis revealed no significant difference in expression of PGR-A and PGR-B \nin ovarian endometriosis compared with control endometrium despite indication of \nselective progesterone resistance (AKR1C1 and AKR1C3).\nKhan et al.42,43 Genomic expressional profile of ectopic tissue differs from that of eutopic, suggestive of \ndifferential regulation in genes involved in physiological functions including progesterone \naction in inflammation, cell cycle, and death, along with relative downregulation of \nPGR in the secretory phase of ectopic endometrium, which is suggestive of relative \nsuppression of progesterone action in ectopic lesion.\nBedaiwy et al.44 Abundance and localisation of progesterone receptor isoforms in endometrium in \nfemales with and without endometriosis and in peritoneal and ovarian endometriotic \nimplants revealed PGR-A as the predominant isoform in peritoneal endometriosis, while \nboth PGR-A and PGR-B were detected in ovarian endometriosis. However, PGR-A \nlevels were significantly elevated in ovarian endo-metriosis compared with peritoneal \nendometriosis.\n17β-HSD: 17-β-hydroxysteroid dehydrogenase; 17β-HSD2: 17-β-hydroxysteroid dehydrogenase Type 2; \nAKR1C1: aldo-keto reductase family 1 member C1; AKR1C3: aldo-keto reductase family 1 member C3; COX-\n2: cyclo-oxygenase-2; MAPK: mitogen-activated protein kinase; mRNA: messenger RNA; NF-κB: nuclear \nfactor κ-light-chain-enhancer of activated B cells; PGR: progesterone receptor.\nTable 1: A chronicle of reports regarding progesterone resistance in endometriotic lesion.\nReview\n\nCreative Commons Attribution-Non Commercial 4.0  ●  August 2022  ●  Reproductive Health\n59\nName with year Major relevant observation\nJones et al.35 No marked difference in PGR expressions between normal endometrium and eutopic \nendometrium during endometriosis. \nAttia et al.6 PGR-A and PGR-B detected in eutopic endometrial samples, with increased levels in the \npre-ovulatory phase with near normal cyclical variation. \nIgarashi et al.47 Eutopic endometriotic endometrium of proliferative phase showed significantly lower \nPGR-B:PGR-A ratio than that in normal endometrium.  \nMatsuzaki et al.38 In eutopic endometrium from patients with deep endometriosis, 17β-HSD2 expression \nin epithelial cells was significantly increased during the early, middle, and late secretory \nphases compared with the late proliferative phase. No such difference was detected in \ncontrol endometrium.\nBurney et al.48 Transcriptome analysis revealed reduced progesterone response in the transition \nfrom the proliferative to secretory phases in eutopic endometrium of females with \nendometriosis compared with normal endometrium.\nAghajanova et al.49,50 Isolated hESF from mid-secretory endometrium with and without endometriosis \npassaged in vitro and exposed to 8-Br-cAMP or progesterone displayed lower \nexpression of decidualisation markers (IGFBP1 and prolactin) by hESF cells from \nfemales with endometriosis versus those without endometriosis in response to 8-Br-\ncAMP but not to progesterone. Decreased 3β-HSD1 and 17β-HSD2, and increased \n17β-HSD1 with a shift towards an estrogenic milieu in hESF cells of eutopic endometrium \nof endometriosis. The normal response of hESF to progesterone, which involves a \ntightly regulated kinetic cascade of PGR and MAPK signalling pathways, resulting in \ndeciualisation was not established by progesterone in hESF cells of endometriosis.\nGentilini et al.51 Both PGR-A and PGR-B expressed in endometrial stromal cells derived from females \nwith and without endometriosis and grown as monolayers on plastic in 10% FBS \ncontaining medium was comparable.\nZelenko et al.23 The study revealed a blunted proliferative-to-secretory transition in early secretory \nphase endometrium of endometriosis, sugges-tive of progesterone resistance in \nendometrium of females with endometriosis.\nBedaiwy et al.44 In eutopic endometrium, levels of PGR-A were significantly elevated in females with \nendometriosis compared with females without disease, regardless of menstrual phase. \nEndometriotic lesions and eutopic endometrium from females with endometriosis are \nuniform in a PGR-A-dominant state.\nBarragan et al.30 eSFs from endometriosis displayed a pro-inflammatory and progesterone resistance \nphenotype not detected in normal eSFs. The progesterone resistance in eSFs inherited \nfrom endometrial mesenchymal cells in endometrosis. \nAnupa et al.52 Higher expression of 17β-HSD1 and PGR-A in eutopic endometrium in endometriosis \ncompared with normal endometrium, particularly during the secretory phase of the \nmenstrual cycle. Dysregulated 17β-HSD1 expression along with alterations in the PGR-\nA:PGR-B ratio, resulting in hyperoestrogenism and progesterone resistance during the \nsecretory phase of the menstrual cycle, rather than an anomaly in aromatase expression \nas hallmarks of eutopic endometrium of patients with ovarian endometriosis who are \ninfertile. Also, revealed that fertility and menstrual cycle histories exert differential \neffects on steroid physiology in endometrium from endometriosis patients compared \nwith control subjects.\n8-Br-cAMP; 8-bromoadenosine 3',5'-cyclic monophosphate; 17β-HSD1: 17-β-hydroxysteroid dehydrogenase \nType 1; 17β-HSD2: 17-β-hydroxysteroid dehydrogenase Type 2; eSF: endometrial stromal fibroblasts; FB: \nfibroblast; hESF: human endometrial stromal fibroblasts; IGFBP1: insulin-like growth factor-binding protein 1; \nMAPK: mitogen-activated protein kinase; PGR: progesterone receptor.\nTable 2: Summary of selected reports regarding progesterone resistance in eutopic endometrium during \nendometriosis.\nReview\n\n60\nReproductive Health  ●  August 2022  ●  Creative Commons Attribution-Non Commercial 4.0\nendometrium.44,47,53 On the contrary, several \nstudies failed to substantiate these findings. A \ncyclical variation in PGR expression in eutopic \nendometrium from females with endometriosis, \nwhich was comparable to normal cyclical \nendometriumm was reported in an early report.34 \nFurther, several studies failed to mark any \nnotable difference in the expression of PGR-A \nand PGR-B expression in normal and  \neutopic endometrium.6,35,51 \nThe reported inconsistencies in results of the \nprevious studies on endometrial progesterone \nreceptivity might have resulted from differences \nin the technical details (e.g., details of tissue \ncollection and handling) and the lack of a \ncategorical consideration of the relative effects \nof fertility and menstrual histories on PGR \nexpression and actions in the endometrium \nof patients with and without endometriosis.52 \nMoreover, the reported studies on PGR response \nused isolated cells maintained in a 2D culture \nsystem, which might be an inadequate model \nfor addressing the core issue of progesterone \nresistance due to the fact that such isolated cells \noften lose their differential behaviour typically \nseen in the tissue.31,49,50,54 \nAdditionally, the statistical design and clinical \ndetails in a few studies were not foolproof. \nThe Endometriosis Phenome (and Biobanking) \nHarmonisation Project (EPHect) guidelines \nhighlight the necessity of developing a \nconsensus on the standardisation and \nharmonisation of phenotypic surgical and clinical \ndata and biological sample handling methods in \nendometriosis research.55,56 In a recent controlled \nstudy conducted according to EPHect guidelines, \nlower levels of expression of aromatase and \noestrogen receptor β along with higher 17β-HSD1 \nand PGR-A in endometrium of females with \novarian endometriosis was observed.52 Thus, \ndysregulated expression of 17β-HSD1 and PGR \nresults in hyperoestrogenism and progesterone \nresistance during the secretory phase of the \nmenstrual cycle, rather than an anomaly in \naromatase expression, was the hallmark of \neutopic endometrium from patients with ovarian \nendometriosis.52 It is now evident that fertility \nand menstrual cycle histories exert differentiating \neffects on endometrial physiology in females  \nwith endometriosis, vis-à-vis normal  \nhealthy endometrium.42,43,52\nMECHANISMS OF PROGESTERONE \nRESISTANCE IN ENDOMETRIOSIS \nCollectively, it appears from different lines \nof evidence available that progesterone \nresistance in endometriosis is not an ‘all-or-none’ \nphenomenon, and that ectopic tissue exhibits \nhigher order of progesterone resistance than \neutopic tissue in a relative scale. Suppression \nof PGR expression and activity in target cells \nmay potentially take place due to interference in \ntranscriptional, post-transcriptional, and post-\ntranslational events, and at the level of protein \nstability. These events can reportedly be affected \nin endometriosis;23,57-61 however, progesterone \nreceptor polymorphisms are not related to \nsusceptibility to endometriosis.62 Fundamentally, \nit depends on genetic background, natural \nhistory of development of the individual, and the \norgan and macro- to micro-environmental details. \nIn an interesting study, Jackson et al.63 \ndemonstrated that PGR-A and PGR-B expression \nin the eutopic endometrium markedly reduced \nover time, between 3 and 15 months, after \ninduction by using a model of experimental \ninduction of endometriosis and implanting \nendometrial tissue into the peritoneal \nenvironment of a baboon.63 In connection to \nthis, McKinnon et al.10 presented an elegant \nmodel explaining how constant exposure \nto the inflammatory ecology in peritoneal \nenvironment may result in suppression of PGR \nexpression and activity. It now appears that \nhuman endometrial fibroblasts display PGR \nresistance and an inflammatory phenotype, \npossibly due to epigenomic modifications in the \nendometrium during endometriosis.10,23,30,31,40,61 \nAlthough PGR gene expressions and PGR \nactions are significantly dysregulated in both \neutopic and ectopic tissues compared with \ncontrol endometrium, the underlying epigenetic \nmechanisms for PGR suppression in the eutopic \ntissue are different from ectopic tissue.57,64\nIMPLICATIONS OF PROGESTERONE \nRESISTANCE IN ENDOMETRIOSIS  \nProgesterone resistance in endometriosis has \nbeen implicated in four clinically challenging \ntrade-offs: pain, infertility, inflammatory \ndisorders, and neoplasm; these impair the quality \nof life of the patients.65 Nearly 10% of females \nReview\n\nCreative Commons Attribution-Non Commercial 4.0  ●  August 2022  ●  Reproductive Health\n61\nReferences\n1. Ghosh D, Sengupta J. Examining \ndiagnostic options and \nclassification systems available for \nendometriosis. EMJ Repro Health. \n2021;7(1):60-71.\n2. Sampson JA. Peritoneal \nendometriosis due to the \nmenstrual dissemination of \nendometrial tissue into the \nperitoneal cavity. Am J Obstet \nGynecol. 1927;14:422-69.\n3. Redwine DB. Was Sampson wrong? \nFertil Steril. 2002;78(4):686-93.\n4. Nisolle M, Donnez J. Peritoneal \nendometriosis, ovarian \nendometriosis, and adenomyotic \nnodules of the rectovaginal septum \nare three different entities. Fertil \nSteril. 1997;68(4):585-96.\n5. Zeitoun K et al. Deficient \n17β-hydroxysteroid \ndehydrogenase type 2 expression \nin endometriosis: failure to \nmetabolize 17β-estradiol. \nJ Clin Endocrinol Metab. \n1998;83(12):4474-80.\n6. Attia GR et al. Progesterone \nreceptor isoform A but not B \nis expressed in endometriosis. \nJ Clin Endocrinol Metab. \n2000;85(8):2897-902.\nof reproductive age have endometriosis, with \nmore than 70% of them affected by chronic \npelvic pain.65 Endometriosis is also a well-\nacknowledged cause of infertility, which is seen \nin 50% of patients with endometriosis with \nnormal ovulation and normo‐spermic partners. \nSevere endometriosis is associated with poor \nembryo implantation rates and pregnancy \nrates in women undergoing in vitro fertilisation \ntreatment.65 Females with endometriosis often \nhave several inflammation‐linked and other \ncomorbidities like uterine fibroid, adenomyosis, \npelvic inflammatory disorder, inflammatory \nbowel disease, systemic lupus erythematosus, \nrheumatoid arthritis, multiple sclerosis, \nfibromyalgia and cardiovascular diseases.65 \nEndometriosis is generally considered benign; \nhowever, unmanaged endometriosis with atypia \nmay result in ovarian and extra-ovarian cancers.66\nBased on generally known progesterone actions \nin target tissues as discussed above and \nshown in Figure 5, it appears that resistance \nof progesterone action may cause the above-\nmentioned endometriosis-associated conditions \nin patients.21,67 Yet, progestin treatment is met \nwith failure in a large number of patients.7,8 Is it \npossible to overcome this resistance with the \nhelp of combinatorial therapies? For example, \ncan the addition of a DNA methyltransferase \ninhibitor to reverse epigenetically suppressed \nPGR expression be helpful? The epigenetic \nmodifications of PGR and progesterone target \ngenes in eutopic and ectopic tissues may, \nhowever, be markedly different.57,64 \nIn primary endometriotic lesions, PGR expression \nis lower than in endometrium, generally \nhaving better prognosis with progesterone \ntreatment. Meanwhile, there was no difference \nin PGR expression as compared with eutopic \nendometrium in recurrent lesions, generally having \npoor prognosis with progesterone treatment.46 \nIt is evident from the above-discussion that \nPGR (both PGR-A and PGR-B) expression status \nis not sufficient to understand the nature of \nprogesterone resistance. Can there be a set of \nnovel and more useful functional parameters? \nHow is PGR expression and response in target \ncells from females with endometriosis affected \nby other linked molecular mechanisms?11,21,26,68,69 \nSeveral such unmet questions point to the \nfact that there is an urgent need for a better \nunderstanding of the nuanced characteristics of \nprogesterone resistance in ectopic and eutopic \ntissue in endometriosis, to innovate better \nmanagement and treatment of progesterone \nresistance in the future.\nCONCLUSION \nIt has been more than half a century since \nthe administration of progestins has become \na part of the normalised procedure to treat \nendometriosis. Nevertheless, its success rate \nis limited as it fails with time and some patients \ndo not respond to this therapy as expected. As \nthe authors have discussed, such progesterone \nresistance occurs due to supressed PGR \nexpression, dysregulated downstream PGR \nactions, or both. In any case, estimated upscaling \nof dosage schedule or by small modifications \nin the molecular design of the drug cannot help \nin circumventing these issues. Success with \navailable combinatorial approach is also not \nvery promising. There is an urgent necessity for \ndeeper and better understanding of the cellular \nand molecular issues related to progesterone \nresistance in endometriosis so that novel \napproaches may be innovated to restore the \nvarious homeostatic mechanisms disrupted by \nprogesterone resistance in ectopic and eutopic \ntissues in endometriosis.\nReview\n\n62\nReproductive Health  ●  August 2022  ●  Creative Commons Attribution-Non Commercial 4.0\n7. Barra F et al. A comprehensive \nreview of hormonal and biological \ntherapies for endometriosis: latest \ndevelopments. Expert Opin Biol \nTher. 2019;19(4):343-60.\n8. Reis FM et al. 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EPHect - \nthe Endometriosis Phenome (and \nBiobanking) Harmonisation Project \n- may be very helpful for clinicians \nand the women they are treating. \nF1000Res. 2017;6:14.\n57. Wu Y et al. Promoter \nhypermethylation of progesterone \nreceptor isoform B (PR-B) in \nendometriosis. Epigenetics. \n2006;1(2):106-11.\n58. Teague EM et al. The role of \nmicroRNAs in endometriosis \nand associated reproductive \nconditions. Hum Reprod Update. \n2010;16(2):142-65.\n59. Meyer JL et al. DNA methylation \npatterns of steroid receptor genes \nESR1, ESR2 and PGR in deep \nendometriosis compromising \nthe rectum. Int J Mol Med. \n2014;33(4):897-904.\n60. Rocha-Junior CV et al. \nProgesterone receptor B (PGR-B) \nis partially methylated in eutopic \nendometrium from infertile women \nwith endometriosis. Reprod Sci. \n2019;26(12):1568-74.\n61. MacLean JA II, Hayashi K. \nProgesterone actions and \nresistance in gynecological \ndisorders. Cells. 2022;11(4):647.\n62. Carneiro PP et al. Association \nof genetic polymorphisms of \nestrogen and progesterone \nreceptors and endometriosis: \nMeta-analysis. J Endometr Pelvic \nPain Disord. 2019;11(1):25-36.\n63. Jackson KS et al. The altered \ndistribution of the steroid hormone \nreceptors and the chaperone \nimmunophilin FKBP52 in a \nbaboon model of endometriosis \nis associated with progesterone \nresistance during the window of \nuterine receptivity. Reprod Sci. \n2007;14(2):137-50.\n64. Esfandiari F et al. Disturbed \nprogesterone signalling in an \nadvanced preclinical model of \nendometriosis. Reprod Biomed \nOnline. 2021;43(1):139-147. \n65. Ghosh D et al. Pathophysiological \nbasis of endometriosis-linked \nstress associated with pain and \ninfertility: a conceptual review. \nReprod Med. 2020;1(1):32-61.\n66. Ghosh D et al. How benign \nis endometriosis: multi-scale \ninterrogation of documented \nevidence. Cur Op Gyn Obs. \n2019;2(1):318-45.\n67. Yang S et al. Progesterone: \nthe ultimate endometrial tumor \nsuppressor. Trends Endocrinol \nMetab. 2011;22(4):145-52.\n68. Li Y et al. Progesterone alleviates \nendometriosis via inhibition \nof uterine cell proliferation, \ninflammation and angiogenesis \nin an immunocompetent \nmouse model. PLoS One. \n2016;11(10):e0165347.\n69. Lode L et al. Abnormal pathways \nin endometriosis in relation to \nprogesterone resistance: a review. \nJ Endometr Pelvic Pain Disord. \n2017;9(4):245-51.\nFOR REPRINT QUERIES PLEASE CONTACT:   INFO@EMJREVIEWS.COM\nReview","source_license":"CC0","license_restricted":false}