{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:15:50Z","timestamp":1791854150949,"version":"4.3.4"},"reference-count":67,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Danish Childhood Cancer Foundation, H\u00f8rslev Foundation","award":["10-001999"],"award-info":[{"award-number":["10-001999"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,25]]},"abstract":"Abstract<\/jats:title>\n \n STUDY QUESTION<\/jats:title>\n Can antioxidant treatment with N-acetylcysteine (NAC) protect ovarian follicles from ischemia-reperfusion injury in xenotransplanted human ovarian tissue?<\/jats:p>\n <\/jats:sec>\n \n SUMMARY ANSWER<\/jats:title>\n Daily administration of NAC for 7\u201312\u2009days post-transplantation reduced ischemia-reperfusion injury and increased follicle survival in human ovarian xenografts by upregulating the antioxidant defense system and exerting anti-inflammatory and antiapoptotic effects.<\/jats:p>\n <\/jats:sec>\n \n WHAT IS KNOWN ALREADY<\/jats:title>\n Freezing of human ovarian tissue is performed with high follicular survival rates but up to 70% of follicles appear to be lost due to hypoxia and ischemia-reperfusion injury during ovarian tissue transplantation (OTT). NAC has been demonstrated to possess antioxidant and antiapoptotic properties, and studies in rodents have shown that intraperitoneal administration of NAC reduces ischemia-reperfusion injury and increases follicle survival in autotransplanted murine ovaries.<\/jats:p>\n <\/jats:sec>\n \n STUDY DESIGN, SIZE, DURATION<\/jats:title>\n Pieces of frozen-thawed human ovarian tissue from 28 women aged 23\u201336\u2009years were transplanted to immunodeficient mice in short- and long-term xenograft studies or cultured in vitro. Three short-term xenograft studies (1-week duration) were performed, in which saline or 150\u2009mg\/kg NAC was administered for 7\u2009days post-transplantation (n\u2009=\u200912 patients per group). Two long-term xenograft studies (4\u2009weeks of duration) were performed. In one of these studies, saline or 150\u2009mg\/kg NAC was administered for 12\u2009days (n\u2009=\u200912 patients per group), while in the other study 50, 150 or 300\u2009mg\/kg NAC was administered for 7\u2009days (n\u2009=\u20098 patients per group). In addition, human ovarian tissue (n\u2009=\u200912 pieces from three patients per group) was cultured with increasing concentrations of NAC (0, 5, 25 and 75\u2009mM) for 4\u2009days in vitro.<\/jats:p>\n <\/jats:sec>\n \n PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n Donated ovarian tissue was obtained from women who had undergone ovarian tissue cryopreservation for fertility preservation at the University Hospital of Copenhagen. Cortical tissue pieces (5 \u00d7 5 \u00d7 1 mm) were transplanted subcutaneously to immunodeficient mice and NAC or saline was injected intraperitoneally. Grafts were retrieved after 1 or 4\u2009weeks and follicle density was assessed. Gene expression analysis of antioxidant defense markers (superoxide dismutase; Sod1\/SOD1, heme oxygenase-1; Hmox1\/HMOX1, catalase; Cat\/CAT), proinflammatory cytokines (tumor necrosis factor-alpha; Tnf-\u03b1, interleukin-1-beta; Il1-\u03b2, interleukin 6; Il6), apoptotic factors (B-cell lymphoma 2; Bcl2\/BCL2, Bcl-2-associated X protein; Bax\/BAX) and angiogenic factors (vascular endothelial growth factor A; Vegfa\/VEGFA, angiopoietin-like 4; Angptl4\/ANGPTL4) was performed in 1-week-old human ovarian xenografts and in cultured human ovarian tissue. Grafts retrieved after 4\u2009weeks were histologically processed and analyzed for vascularization by CD31 immunohistochemical staining, fibrosis by Masson\u2019s Trichrome staining and apoptosis by immunofluorescence using cleaved caspase-3.<\/jats:p>\n <\/jats:sec>\n \n MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n After 1-week grafting, the relative expression of Sod1, Hmox1 and Cat was significantly higher in the group receiving 150\u2009mg\/kg NAC (NAC150-treated group) compared to controls (P\u2009=\u20090.04, P\u2009=\u20090.03, and P\u2009=\u20090.01, respectively), whereas the expression levels of Tnf-\u03b1, Il1-\u03b2 and Il6 were reduced. The Bax\/Bcl2 ratio was also significantly reduced in the NAC150-treated group (P\u2009&lt;\u20090.005). In vitro, the relative gene expression of SOD1, HMOX1 and CAT increased significantly in the human ovarian tissue with increasing concentrations of NAC (P\u2009&lt;\u20090.001 for all genes). However, the expression of VEGFA and ANGPTL4 as well as the BAX\/BCL2 ratio decreased significantly with increasing concentrations of NAC (P\u2009&lt;\u20090.02, P\u2009&lt;\u20090.001 and P\u2009&lt;\u20090.001, respectively). After 4-week grafting, fibrosis measured by collagen content was similar in the NAC150-treated group compared to controls (control: 56.6% \u00b1 2.2; NAC150: 57.6% \u00b1 1.8), whereas a statistically significant reduction in the CD31-positive vessel area was found (control: 0.69% \u00b1 0.08; NAC150: 0.51% \u00b1 0.07; P\u2009&lt;\u20090.02). Furthermore, a reduced immunoreactivity of cleaved caspase-3 was observed in follicles of the NAC150-treated xenografts compared to controls. Follicle density (follicles\/mm3, mean \u00b1 SD) was higher in the NAC150-treated group compared to the control group in the 1-week xenografts (control: 19.5\u2009\u00b1\u200926.3; NAC150: 34.2\u2009\u00b1\u200953.5) and 4-week xenografts (control: 9.3\u2009\u00b1\u200911.0; NAC150: 14.4\u2009\u00b1\u200915.0). Overall, a 2-fold increase in follicle density was observed in the NAC150-group after 1-week grafting where fold changes in follicle density were calculated in relation to grafts from the same patient. Around a 5-fold increase in follicle density was observed in the NAC150 and NAC300 groups after 4-week grafting.<\/jats:p>\n <\/jats:sec>\n \n LARGE SCALE DATA<\/jats:title>\n N\/A<\/jats:p>\n <\/jats:sec>\n \n LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n Follicle density in the human ovarian cortex is highly heterogeneous and can vary 100-fold between cortex pieces from the same woman. A high variability in follicle density within and between treatment groups and patients was found in the current study. Thus, solid conclusions cannot be made. While intraperitoneal injections of NAC appeared to reduce ischemia-reperfusion injury in human ovarian xenografts, different administration routes should be investigated in order to optimize NAC for potential clinical use.<\/jats:p>\n <\/jats:sec>\n \n WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n This is the first study to demonstrate the antioxidant, anti-inflammatory and antiapoptotic properties of NAC in xenotransplanted human ovarian tissue. Therefore, NAC appears to be a promising candidate for protecting ovarian follicles from ischemia-reperfusion injury. This provides the initial steps toward clinical application of NAC, which could potentially reduce the loss of ovarian follicles following OTT.<\/jats:p>\n <\/jats:sec>\n \n STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n We are grateful to the Danish Childhood Cancer Foundation, H\u00f8rslev Foundation, Aase and Einar Danielsen\u2019s Foundation (grant number: 10-001999), Dagmar Marshalls Foundation, Else and Mogens Wedell-Wedellsborgs Foundation, Knud and Edith Eriksens Mindefond, and Fabrikant Einar Willumsens Mindelegat for funding this study. None of the authors have any competing interests to declare.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/humrep\/deaa291","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T11:19:43Z","timestamp":1601896783000},"page":"429-443","source":"Crossref","is-referenced-by-count":48,"title":["N-acetylcysteine protects ovarian follicles from ischemia-reperfusion injury in xenotransplanted human ovarian tissue"],"prefix":"10.1093","volume":"36","author":[{"given":"Hanna \u00d8rnes","family":"Olesen","sequence":"first","affiliation":[{"name":"Laboratory of Reproductive Biology, Fertility Department, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, Copenhagen DK-2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne Elisabeth","family":"Pors","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, Fertility Department, The Juliane Marie Centre for Women, 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