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Variable and sex\u2010specific impacts of ACS on the placenta have been reported and may reflect differing expression profiles of glucocorticoid receptor (GR) isoforms. We therefore examined placental GR isoforms and molecular and structural responses to betamethasone in the clinically relevant sheep pregnancy. Pregnant Merino ewes at 138\u00a0days of gestation (term\u00a0=\u00a0150\u00a0days) received <jats:sc>i.m.<\/jats:sc> injections of saline or 11.6\u00a0mg of betamethasone 48 and 24\u00a0h prior to Caesarean section delivery of lambs and tissue collection. Placental glucocorticoid concentrations were measured using liquid chromatography\u2010tandem mass spectrometry. Markers of GR signalling and placental development and function were measured using histology, western blotting and quantitative real\u2010time PCR. Betamethasone increased diffusion barrier thickness in female placentae only and reduced placental cortisol concentrations in both sexes. Betamethasone increased cytoplasmic GR\u03b1C, GR\u2010P and GR\u03b1D isoforms in female placentae only; neither treatment nor sex impacted nuclear GR isoform expression. Expression of angiogenic genes was higher, whereas that of growth\u2010promoting genes was lower, in betamethasone\u2010exposed placentae, independent of sex. Similarly, expression of endoplasmic reticulum stress genes was lower in betamethasone\u2010exposed than control placentae, whereas those involved in oxidative stress and apoptosis were higher, particularly in females. Betamethasone induced molecular changes in the placenta within 48\u00a0h of exposure. The apoptotic response was heightened in female placentae, possibly driven by higher expression of specific GR isoforms, which contributes to a greater risk of ACS\u2010induced placental insufficiency.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70031-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Betamethasone treatment for pregnancies at risk of preterm delivery not only reduces the risk of neonatal death, but also acts on glucocorticoid receptors (GR) in the placenta, inducing sex\u2010specific changes that may impact function and fetal growth. In this study, we explored sex\u2010specific placental molecular responses to betamethasone in the clinically relevant sheep pregnancy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Betamethasone increased markers of angiogenesis and decreased markers of growth and proliferation in placentae of both sexes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In females only, betamethasone increased expression of the pro\u2010apoptotic GR isoform, GR\u03b1C, which coincided with an enriched pro\u2010apoptotic response and an increased placental diffusion barrier thickness, indicative of placental insufficiency.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our findings highlight that betamethasone induces several molecular changes in the sheep placenta within 48\u00a0h of exposure and supports previous sex\u2010specific findings in other species, indicative of a conserved female response.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp289044","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T03:58:36Z","timestamp":1754884716000},"page":"4867-4886","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex\u2010specific effects of betamethasone on glucocorticoid and apoptotic signalling pathways in the sheep placenta"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-6274","authenticated-orcid":false,"given":"Ashley S.","family":"Meakin","sequence":"first","affiliation":[{"name":"Early Origins of Adult Health Research Group, Clinical and Health Sciences University of South Australia  Adelaide SA Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3594-1455","authenticated-orcid":false,"given":"Mitchell 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