{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:01:50Z","timestamp":1790197310557,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>To evaluate the effects and mechanisms of action of growth hormone (GH) in the recovery of ovarian function in ovarian insufficiency induced by cyclophosphamide (CP) in a mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>After inducing ovarian insufficiency by administering 400 mg\/kg of CP intraperitoneally to 6-week-old ICR mice, the mice were divided into four groups (control, CP, 1 mg\/kg GH, and 2 mg\/kg GH) with 10 mice in each group. GH was administered a week later for 7 days. Five mice from each group were sacrificed the next day, and their ovaries were collected for histological examination. The remaining mice were superovulated for <jats:italic>in vitro<\/jats:italic> fertilization (IVF). The terminal deoxynucleotidyl transferase dUTP-nick end labeling assay was performed to detect apoptosis. Masson\u2019s trichrome staining was used to analyze the degree of fibrosis. To quantify angiogenesis, CD31 immunohistochemistry was performed. Angiogenesis-related gene expression profiles were assessed using quantitative reverse transcription polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CP induced the loss of non-growing (primordial and primary) follicles while GH significantly protected primordial follicles and increased follicular quality. The CP group showed a decrease in fertilization and blastocyst formation rates in IVF. In contrast, the GH treatment group showed dose-dependent enhanced IVF outcomes. Furthermore, GH treatment decreased apoptosis and stromal fibrosis and increased angiogenesis. Many genes involved in angiogenesis, especially Leptin (<jats:italic>Lep<\/jats:italic>), platelet endothelial cell adhesion molecule 1 (<jats:italic>Pecam-1<\/jats:italic>), and angiogenin (<jats:italic>Ang<\/jats:italic>) were up-regulated in the GH treatment groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>GH treatment may promote the recovery of ovarian function in ovarian insufficiency induced by the administration of CP via decreasing apoptosis and stromal fibrosis and upregulating <jats:italic>Lep<\/jats:italic>, <jats:italic>Pecam-1<\/jats:italic>, and <jats:italic>Ang<\/jats:italic> genes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1184977","type":"journal-article","created":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T09:59:30Z","timestamp":1696327170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The effect of growth hormone on ovarian function recovery in a mouse model of ovarian insufficiency"],"prefix":"10.3389","volume":"14","author":[{"given":"Su Mi","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Young","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Hee","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewang","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hyang","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Ryeol","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.09.006","article-title":"Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: esmo clinical practice guidelines(\u2020)","volume":"31","author":"Lambertini","year":"2020","journal-title":"Ann Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(17)30677-0","article-title":"Cancer incidence and mortality among young adults aged 20-39 years worldwide in 2012: A population-based study","volume":"18","author":"Fidler","year":"2017","journal-title":"Lancet Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1530\/eje-20-1178","article-title":"Therapy of endocrine disease: novel protection and treatment strategies for chemotherapy-associated ovarian damage","volume":"184","author":"Xiong","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-016-0467-z","article-title":"Premature ovarian insufficiency: the context of long-term effects","volume":"39","author":"Podfigurna-Stopa","year":"2016","journal-title":"J Endocrinol Invest"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1200\/jco.2018.78.1914","article-title":"Fertility preservation in patients with cancer: asco clinical practice guideline update","volume":"36","author":"Oktay","year":"2018","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s13048-021-00929-3","article-title":"Ovarian tissue cryopreservation in a patient with breast cancer during pregnancy: A case report","volume":"14","author":"Cheng","year":"2021","journal-title":"J Ovarian Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2019.09.013","article-title":"Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: A committee opinion","volume":"112","year":"2019","journal-title":"Fertil Steril"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.03.284","article-title":"Eso-Esmo 4th international consensus guidelines for breast cancer in young women (Bcy4)","volume":"31","author":"Paluch-Shimon","year":"2020","journal-title":"Ann Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2850","DOI":"10.3390\/ijms23052850","article-title":"Stem cell therapy: from idea to clinical practice","volume":"23","author":"Mousaei Ghasroldasht","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00502","article-title":"Application of growth hormone in in vitro fertilization","volume":"10","author":"Xu","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/234014","article-title":"Growth hormone and reproduction: A review of endocrine and autocrine\/paracrine interactions","volume":"2014","author":"Hull","year":"2014","journal-title":"Int J Endocrinol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00777","article-title":"Growth hormone and insulin-like growth factor action in reproductive tissues","volume":"10","author":"Ipsa","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00775","article-title":"The effect of growth hormone on the clinical outcomes of poor ovarian reserve patients undergoing in vitro fertilization\/intracytoplasmic sperm injection treatment: A retrospective study based on Poseidon criteria","volume":"10","author":"Cai","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e6443","DOI":"10.1097\/md.0000000000006443","article-title":"The influence of different growth hormone addition protocols to poor ovarian responders on clinical outcomes in controlled ovary stimulation cycles: A systematic review and meta-analysis","volume":"96","author":"Li","year":"2017","journal-title":"Med (Baltimore)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.fertnstert.2020.03.007","article-title":"Growth hormone cotreatment for poor responders undergoing in vitro fertilization cycles: A systematic review and meta-analysis","volume":"114","author":"Cozzolino","year":"2020","journal-title":"Fertil Steril"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e0140055","DOI":"10.1371\/journal.pone.0140055","article-title":"Growth hormone ameliorates the radiotherapy-induced ovarian follicular loss in rats: impact on oxidative stress, apoptosis and Igf-1\/Igf-1r axis","volume":"10","author":"Mahran","year":"2015","journal-title":"PloS One"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2016.3326","article-title":"Growth hormone treatment of premature ovarian failure in a mouse model via stimulation of the notch-1 signaling pathway","volume":"12","author":"Liu","year":"2016","journal-title":"Exp Ther Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.ejogrb.2011.02.012","article-title":"Growth hormone reduces tissue damage in rat ovaries subjected to torsion and detorsion: biochemical and histopathologic evaluation","volume":"157","author":"Yigiter","year":"2011","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1186\/s13287-019-1490-8","article-title":"Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting Mt1","volume":"10","author":"Huang","year":"2019","journal-title":"Stem Cell Res Ther"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.3390\/molecules25061302","article-title":"Treatment with subcritical water-hydrolyzed citrus pectin ameliorated cyclophosphamide-induced immunosuppression and modulated gut microbiota composition in Icr mice","volume":"25","author":"Chen","year":"2020","journal-title":"Molecules"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2008.04.007","article-title":"The effect of growth hormone on ovarian follicular response and oocyte nuclear maturation in young and aged mice","volume":"111","author":"Semiz","year":"2009","journal-title":"Acta Histochem"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.1150251","article-title":"Populations of granulosa cells in small follicles of the sheep ovary","volume":"115","author":"Lundy","year":"1999","journal-title":"J Reprod Fertil"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2005.08.062","article-title":"Efficiency of equilibrium cooling and vitrification procedures for the cryopreservation of ovarian tissue: comparative analysis between human and animal models","author":"Gandolfi","year":"2006","journal-title":"Fertil Steril"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dev222","article-title":"A combination of simvastatin and methylprednisolone improves the quality of vitrified-warmed ovarian tissue after auto-transplantation","volume":"30","author":"Lee","year":"2015","journal-title":"Hum Reprod"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0166782","DOI":"10.1371\/journal.pone.0166782","article-title":"Effects of angiopoietin-2 on transplanted mouse ovarian tissue","volume":"11","author":"Youm","year":"2016","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12088","article-title":"Automated quantification of renal fibrosis with sirius red and polarization contrast microscopy","volume":"2","author":"Street","year":"2014","journal-title":"Physiol Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1186\/s12885-018-4180-5","article-title":"Cd31 and Vegf are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma","volume":"18","author":"Schl\u00fcter","year":"2018","journal-title":"BMC Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/01.Aog.0000451757.51964.98","article-title":"Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women","volume":"124","year":"2014","journal-title":"Obstet Gynecol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100112","article-title":"How I perform fertility preservation in breast cancer patients","volume":"6","author":"Razeti","year":"2021","journal-title":"ESMO Open"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1040503","article-title":"Growth hormone in fertility and infertility: mechanisms of action and clinical applications","volume":"13","author":"Chang","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202534","article-title":"Growth hormone ameliorates the age-associated depletion of ovarian reserve and decline of oocyte quality via inhibiting the activation of Fos and Jun signaling","volume":"13","author":"Liu","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"eabn4564","DOI":"10.1126\/sciadv.abn4564","article-title":"Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary","volume":"8","author":"Umehara","year":"2022","journal-title":"Sci Adv"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.198931","article-title":"Ovarian fibrosis: a phenomenon of concern","volume":"130","author":"Zhou","year":"2017","journal-title":"Chin Med J (Engl)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dem027","article-title":"Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury","volume":"22","author":"Meirow","year":"2007","journal-title":"Hum Reprod"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000259593.07661.1e","article-title":"Endothelial cell migration during angiogenesis","volume":"100","author":"Lamalice","year":"2007","journal-title":"Circ Res"},{"key":"B36","article-title":"Angiogenic factors and ovarian follicle development","volume":"6","author":"Bruno","year":"2009","journal-title":"Anim Reprod"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00450","article-title":"The role of growth hormone on ovarian functioning and ovarian angiogenesis","volume":"10","author":"Devesa","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.585887","article-title":"Leptin and obesity: role and clinical implication","volume":"12","author":"Obradovic","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/jci32239","article-title":"Angiogenesis modulates adipogenesis and obesity","volume":"117","author":"Cao","year":"2007","journal-title":"J Clin Invest"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.281.5383.1683","article-title":"Biological action of leptin as an angiogenic factor","volume":"281","author":"Sierra-Honigmann","year":"1998","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","first-page":"bqaa204","DOI":"10.1210\/endocr\/bqaa204","article-title":"The importance of leptin to reproduction","volume":"162","author":"Childs","year":"2021","journal-title":"Endocrinology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2016.03.012","article-title":"Endothelial Pecam-1 and its function in vascular physiology and atherogenic pathology","volume":"100","author":"Chistiakov","year":"2016","journal-title":"Exp Mol Pathol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/moh.0000000000000239","article-title":"Endothelial functions of platelet\/endothelial cell adhesion molecule-1 (Cd31)","volume":"23","author":"Lertkiatmongkol","year":"2016","journal-title":"Curr Opin Hematol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00524.2001","article-title":"Involvement of human pecam-1 in angiogenesis and in vitro endothelial cell migration","volume":"282","author":"Cao","year":"2002","journal-title":"Am J Physiol Cell Physiol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/onc.2014.2","article-title":"Angiogenin promotes tumoral growth and angiogenesis by regulating matrix metallopeptidase-2 expression via the Erk1\/2 pathway","volume":"34","author":"Miyake","year":"2015","journal-title":"Oncogene"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7270.2008.00442.x","article-title":"Mechanisms of action of angiogenin","volume":"40","author":"Gao","year":"2008","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2022.01.017","article-title":"Angiogenin promotes angiogenesis via the endonucleolytic decay of Mir-141 in colorectal cancer","volume":"27","author":"Weng","year":"2022","journal-title":"Mol Ther Nucleic Acids"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1184977\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T09:59:33Z","timestamp":1696327173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1184977\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,3]]},"references-count":47,"alternative-id":["10.3389\/fendo.2023.1184977"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1184977","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,3]]},"article-number":"1184977"}}