{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:03:24Z","timestamp":1787954604835,"version":"build-2784847793"},"reference-count":29,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T00:00:00Z","timestamp":1617753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000325","name":"Wellbeing of Women","doi-asserted-by":"publisher","award":["RTF510, RG1073, RG2137"],"award-info":[{"award-number":["RTF510, RG1073, RG2137"]}],"id":[{"id":"10.13039\/501100000325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) are distressing conditions without effective treatments. The luminal epithelium (LE) is integral in determining receptivity of the endometrium, whereas functionalis glands and stroma aid in nurturing early embryo development. Calcium signalling pathways are known to be of vital importance to embryo implantation and pregnancy establishment, and anterior gradient protein 3 (AGR3) and S100 calcium-binding protein P (S100P) are involved with these pathways. We initially examined 20 full-thickness endometrial biopsies from premenopausal women across the menstrual cycle to characterize levels of AGR3 protein in each endometrial sub-region at the cellular level. A further 53 endometrial pipelle biopsies collected in the window of implantation were subsequently assessed to determine differential endometrial AGR3 and S100P levels relevant to RIF (n = 13) and RPL (n = 10) in comparison with parous women (n = 30) using immunohistochemistry. Significantly higher AGR3 and S100P immunostaining was observed in ciliated cells of the LE of women with recurrent reproductive failure compared with parous women, suggesting aberrant subcellular location-associated pathophysiology for these conditions. The nuclear localisation of S100P may allow transcriptional regulatory function, which is necessary for implantation of a viable pregnancy. Further work is thus warranted to assess their utility as diagnostic\/therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms22083835","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T11:31:59Z","timestamp":1617795119000},"page":"3835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3633-1592","authenticated-orcid":false,"given":"Nicola","family":"Tempest","sequence":"first","affiliation":[{"name":"Centre for Women\u2019s Health Research, Department of Women\u2019s and Children\u2019s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"},{"name":"Liverpool Women\u2019s NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"},{"name":"Hewitt Centre for Reproductive Medicine, Liverpool Women\u2019s NHS Foundation Trust, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Batchelor","sequence":"additional","affiliation":[{"name":"Centre for Women\u2019s Health Research, Department of Women\u2019s and Children\u2019s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Hill","sequence":"additional","affiliation":[{"name":"Centre for Women\u2019s Health Research, Department of Women\u2019s and Children\u2019s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannan","family":"Al-Lamee","sequence":"additional","affiliation":[{"name":"Centre for Women\u2019s Health Research, Department of Women\u2019s and Children\u2019s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"},{"name":"Hewitt Centre for Reproductive Medicine, Liverpool Women\u2019s NHS Foundation Trust, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2275-6664","authenticated-orcid":false,"given":"Josephine","family":"Drury","sequence":"additional","affiliation":[{"name":"Centre for Women\u2019s Health Research, Department of Women\u2019s and Children\u2019s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8802-4706","authenticated-orcid":false,"given":"Andrew J.","family":"Drakeley","sequence":"additional","affiliation":[{"name":"Hewitt Centre for Reproductive Medicine, Liverpool Women\u2019s NHS Foundation Trust, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0270-0150","authenticated-orcid":false,"given":"Dharani K.","family":"Hapangama","sequence":"additional","affiliation":[{"name":"Centre for Women\u2019s Health Research, Department of Women\u2019s and Children\u2019s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"},{"name":"Liverpool Women\u2019s NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1093\/humrep\/del305","article-title":"Investigation and treatment of repeated implantation failure following IVF-ET","volume":"21","author":"Margalioth","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.rbmo.2019.10.014","article-title":"How common is real repeated implantation failure? An indirect estimate of the prevalence","volume":"40","author":"Busnelli","year":"2020","journal-title":"Reprod. Biomed. Online"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Busnelli, A., Somigliana, E., Cirillo, F., Baggiani, A., and Levi-Setti, P.E. (2021). Efficacy of therapies and interventions for repeated embryo implantation failure: A systematic review and meta-analysis. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-81439-6"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.rbmo.2013.12.006","article-title":"What exactly do we mean by \u2018recurrent implantation failure\u2019? A systematic review and opinion","volume":"28","author":"Polanski","year":"2014","journal-title":"Reprod. Biomed. Online"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"ESHRE Guideline Group on RPL, Bender Atik, R., Christiansen, O.B., Elson, J., Kolte, A.M., Lewis, S., Middeldorp, S., Nelen, W., Peramo, B., and Quenby, S. (2018). ESHRE guideline: Recurrent pregnancy loss. Hum. Reprod. Open., 2018, hoy004.","DOI":"10.1093\/hropen\/hoy004"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Practice Committee of the American Society for Reproductive Medicine (2013). Definitions of infertility and recurrent pregnancy loss: A committee opinion. Fertil. Steril., 99, 63.","DOI":"10.1016\/j.fertnstert.2012.09.023"},{"key":"ref_7","unstructured":"Royal College of Obstetricians and Gynaecologists (2011). The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage. Green Top. Guidel., 17, 1\u201317."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.rbmo.2013.08.011","article-title":"Recurrent implantation failure: Definition and management","volume":"28","author":"Coughlan","year":"2014","journal-title":"Reprod. Biomed. Online"},{"key":"ref_9","first-page":"269","article-title":"Biochemical pregnancy during assisted conception: A little bit pregnant","volume":"5","author":"Annan","year":"2013","journal-title":"J. Clin. Med. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1095\/biolreprod65.5.1311","article-title":"Developmental biology of uterine glands","volume":"65","author":"Gray","year":"2001","journal-title":"Biol. Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.fertnstert.2014.04.005","article-title":"In the secretory endometria of women, luminal epithelia exhibit gene and protein expressions that differ from those of glandular epithelia","volume":"102","author":"Evans","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/03009738009179166","article-title":"Scanning electron microscopy of the responses of postmenopausal endometrium to treatment with estriol and estriolprogesterone","volume":"85","author":"Nilsson","year":"1980","journal-title":"Ups. J. Med. Sci."},{"key":"ref_13","first-page":"66","article-title":"Scanning electron microscopy of the human normal endometrium","volume":"7","author":"Baraggino","year":"1980","journal-title":"Clin. Exp. Obs. Gynecol."},{"key":"ref_14","unstructured":"Strauss, J., and Barbieri, R. (2019). Yen and Jaffe\u2019s Reproductive Endocrinology, Elsevier."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1093\/HUMREP\/10.6.1579","article-title":"The signals and molecular pathways involved in implantation, a symbiotic interaction between blastocyst and endometrium involving adhesion and tissue invasion","volume":"10","author":"Tabibzadeh","year":"1995","journal-title":"Hum. Reprod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.ceca.2010.12.003","article-title":"Calcium signaling in placenta","volume":"49","author":"Baczyk","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.bbamcr.2018.08.005","article-title":"Establishing life is a calcium-dependent TRiP: Transient receptor potential channels in reproduction","volume":"1865","author":"Vriens","year":"2018","journal-title":"Biochim. Biophys. Acta. Mol. Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1165\/rcmb.2014-0318OC","article-title":"The Endoplasmic Reticulum Resident Protein AGR3. Required for Regulation of Ciliary Beat Frequency in the Airway","volume":"53","author":"Bonser","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31459","DOI":"10.18632\/oncotarget.25838","article-title":"High AGR2 protein is a feature of low grade endometrial cancer cells","volume":"9","author":"Kamal","year":"2018","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1111\/febs.12118","article-title":"Anterior gradient 2 and 3\u2014Two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells","volume":"280","author":"Bu","year":"2013","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Garczyk, S., von Stillfried, S., Antonopoulos, W., Hartmann, A., Schrauder, M.G., Fasching, P.A., Anzeneder, T., Tannapfel, A., Ergonenc, Y., and Knuchel, R. (2015). AGR3 in breast cancer: Prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122106"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/j.1432-1033.1992.tb17080.x","article-title":"S100P, a novel Ca(2+)-binding protein from human placenta. cDNA cloning, recombinant protein expression and Ca2+ binding properties","volume":"207","author":"Becker","year":"1992","journal-title":"Eur. J. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.fertnstert.2009.07.1667","article-title":"Calcium-binding protein S100P is highly expressed during the implantation window in human endometrium","volume":"94","author":"Tong","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_24","first-page":"562","article-title":"The life and works of S100P\u2014From conception to cancer","volume":"6","author":"Prica","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1093\/humrep\/der412","article-title":"Aberrant expression of metastasis-inducing proteins in ectopic and matched eutopic endometrium of women with endometriosis: Implications for the pathogenesis of endometriosis","volume":"27","author":"Hapangama","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/S0002-9378(16)33500-1","article-title":"Dating the endometrial biopsy","volume":"122","author":"Noyes","year":"1975","journal-title":"Am. J. Obstet Gynecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1055\/s-2008-1035889","article-title":"Histologic endometrial findings in patients on the day of planned embryo transfer","volume":"47","author":"Dallenbach","year":"1987","journal-title":"Geburtshilfe Frauenheilkd."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1093\/humrep\/det285","article-title":"SSEA-1 isolates human endometrial basal glandular epithelial cells: Phenotypic and functional characterization and implications in the pathogenesis of endometriosis","volume":"28","author":"Valentijn","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/bjc.2016.16","article-title":"Androgen receptors are acquired by healthy postmenopausal endometrial epithelium and their subsequent loss in endometrial cancer is associated with poor survival","volume":"114","author":"Kamal","year":"2016","journal-title":"Br. J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3835\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:34:17Z","timestamp":1760362457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,7]]},"references-count":29,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22083835"],"URL":"https:\/\/doi.org\/10.3390\/ijms22083835","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,7]]}}}