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Patients with POI, especially at the onset of pubertal development, experience significant endocrine complications, including delayed growth, elevated risks of obesity and diabetes, and accelerated cardiovascular, musculoskeletal and neurological disorders as adults. The only approved pharmacological treatment for POI is an off-label prescribed hormone replacement therapy, which does not replace physiologically functioning ovaries. To restore production of ovarian hormones and protect against immune-mediated injury, we developed a hydrogel-based capsule for implantation of donor ovarian tissue. We evaluated the restoration of ovarian endocrine function in ovariectomized immunodeficient (NOD scid gamma, NSG) mice implanted with encapsulated xenografts over 20 weeks through daily vaginal cytology, hormone measurements and histological analysis of explanted human xenografts. The encapsulated xenografts integrated into the murine hypothalamus-pituitary-gonad (HPG) axis responding to circulating murine gonadotropins and restoring ovarian endocrine function. As controls, we implanted non encapsulated human ovarian xenografts comparable in size. Without the need for exogeneous stimulation, the estrous cyclicity resumed in both groups of mice 12 weeks post implantation and all mice regularly cycled experiencing between 3 to 8 estrous cycles in 20 weeks. The levels of estradiol gradually increased reaching on average 50pg\/mL 20 weeks post implantation. Morphological analysis of the encapsulated grafts revealed presence of large antral follicles, \u223c3mm in diameter, consistent with regular cyclicity and measurable levels of circulating hormones. This work demonstrates that endocrine function of encapsulated human ovarian tissue was not affected by the encapsulation and integrated with the host physiology similarly to the non-encapsulated controls.<\/jats:p>","DOI":"10.1101\/2025.02.27.640622","type":"posted-content","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T23:00:21Z","timestamp":1741042821000},"source":"Crossref","is-referenced-by-count":1,"title":["Restoration of ovarian endocrine function with encapsulated immune isolated human ovarian xenograft in ovariectomized mice"],"prefix":"10.64898","author":[{"given":"Margaret A.","family":"Brunette","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"},{"name":"Division of Pediatric and Adolescent Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica A.","family":"Wall","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delaney","family":"Sinko","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan H.","family":"Machlin","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle M.","family":"Blevins","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansen","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bipasha","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilia","family":"Cascalho","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University Cleveland, OH, United States"},{"name":"Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasantha","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics & Communicable Diseases, University of Michigan, Ann Arbor, MI, United States"},{"name":"Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariella","family":"Shikanov","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States"},{"name":"Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, United States"},{"name":"Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041111564160000_2025.02.27.640622v1.1","unstructured":"National Cancer Institute, NCCR*Explorer: An interactive website for NCCR cancer statistics (2023) (available at https:\/\/nccrexplorer.ccdi.cancer.gov.)."},{"key":"2026041111564160000_2025.02.27.640622v1.2","unstructured":"American Cancer Society, American Cancer Society. 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