{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T04:01:48Z","timestamp":1793678508772,"version":"4.5.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671422"],"award-info":[{"award-number":["81671422"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased <jats:italic>INSR<\/jats:italic> expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased <jats:italic>FSHR<\/jats:italic> expression and increased <jats:italic>LHCGR<\/jats:italic> expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that <jats:italic>FSHR<\/jats:italic> and <jats:italic>LHCGR<\/jats:italic> dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in <jats:italic>INSR<\/jats:italic>, <jats:italic>FSHR<\/jats:italic>, and <jats:italic>LHCGR<\/jats:italic> expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients.<\/jats:p>","DOI":"10.3389\/fendo.2021.701590","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T12:48:11Z","timestamp":1628858891000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Effects of Metformin on Reproductive, Endocrine, and Metabolic Characteristics of Female Offspring in a Rat Model of Letrozole-Induced Polycystic Ovarian Syndrome With Insulin Resistance"],"prefix":"10.3389","volume":"12","author":[{"given":"Yidong","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmq001","article-title":"Impaired Glucose Tolerance, Type 2 Diabetes and Metabolic Syndrome in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis","volume":"16","author":"Moran","year":"2010","journal-title":"Hum Reprod Update"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2004-0004","article-title":"The Molecular-Genetic Basis of Functional Hyperandrogenism and the Polycystic Ovary Syndrome","volume":"26","author":"Escobar-Morreale","year":"2005","journal-title":"Endocr Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.24","article-title":"Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment","volume":"14","author":"Escobar-Morreale","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2010.03956.x","article-title":"PCOS Forum: Research in Polycystic Ovary Syndrome Today and Tomorrow","volume":"74","author":"Pasquali","year":"2011","journal-title":"Clin Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2011.03.021","article-title":"Pregnancy Outcomes in Women With Polycystic Ovary Syndrome: A Meta Analysis","volume":"204","author":"Kjerulff","year":"2011","journal-title":"Am J Obstet Gynecol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1477-7827-11-56","article-title":"Obstetric Complications in Women With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis","volume":"11","author":"Qin","year":"2013","journal-title":"Reprod Biol Endocrin"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dml036","article-title":"A Meta-Analysis of Pregnancy Outcomes in Women With Polycystic Ovary Syndrome","volume":"12","author":"Boomsma","year":"2006","journal-title":"Hum Reprod Update"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000000852","article-title":"Implications of Polycystic Ovary Syndrome for Pregnancy and for the Health of Offspring","volume":"125","author":"Doherty","year":"2015","journal-title":"Obstet Gynecol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"16057","DOI":"10.1038\/nrdp.2016.57","article-title":"Polycystic Ovary Syndrome","volume":"2","author":"Azziz","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.mce.2012.10.009","article-title":"Genetics of the Polycystic Ovary Syndrome","volume":"373","author":"Kosova","year":"2013","journal-title":"Mol Cell Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-1333","article-title":"High Prevalence of Metabolic Syndrome in First-Degree Male Relatives of Women With Polycystic Ovary Syndrome is Related to High Rates of Obesity","volume":"94","author":"Coviello","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.111.097808","article-title":"Rodent Models for Human Polycystic Ovary Syndrome","volume":"86","author":"Walters","year":"2012","journal-title":"Biol Reprod"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1693","article-title":"Continuous Administration of a P450 Aromatase Inhibitor Induces Polycystic Ovary Syndrome With a Metabolic and Endocrine Phenotype in Female Rats at Adult Age","volume":"154","author":"Maliqueo","year":"2013","journal-title":"Endocrinology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-03218","article-title":"Antiandrogen Treatment Ameliorates Reproductive and Metabolic Phenotypes in the Letrozole-Induced Mouse Model of PCOS","volume":"159","author":"Ryan","year":"2018","journal-title":"Endocrinology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2018.01.008","article-title":"Differential Insulin and Steroidogenic Signaling in Insulin Resistant and non-Insulin Resistant Human Luteinized Granulosa Cells-A Study in PCOS Patients","volume":"178","author":"Belani","year":"2018","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.fertnstert.2011.11.036","article-title":"All Women With PCOS Should be Treated for Insulin Resistance","volume":"97","author":"Marshall","year":"2012","journal-title":"Fertil Steril"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.1.5393","article-title":"Prevalence and Predictors of Risk for Type 2 Diabetes Mellitus and Impaired Glucose Tolerance in Polycystic Ovary Syndrome: A Prospective, Controlled Study in 254 Affected Women","volume":"84","author":"Legro","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1210\/er.2011-1034","article-title":"Insulin Resistance and the Polycystic Ovary Syndrome Revisited: An Update on Mechanisms and Implications","volume":"33","author":"Diamanti-Kandarakis","year":"2012","journal-title":"Endocr Rev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05679.x","article-title":"Metformin in Polycystic Ovary Syndrome","volume":"1205","author":"Diamanti-Kandarakis","year":"2010","journal-title":"Ann N Y Acad Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmv025","article-title":"Metformin and Lifestyle Modification in Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis","volume":"21","author":"Naderpoor","year":"2015","journal-title":"Hum Reprod Update"},{"key":"B21","doi-asserted-by":"publisher","first-page":"Cd013505","DOI":"10.1002\/14651858.CD013505","article-title":"Metformin for Ovulation Induction (Excluding Gonadotrophins) in Women With Polycystic Ovary Syndrome","volume":"12","author":"Sharpe","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(19)30002-6","article-title":"Use of Metformin to Treat Pregnant Women With Polycystic Ovary Syndrome (PregMet2): A Randomised, Double-Blind, Placebo-Controlled Trial","volume":"7","author":"L\u00f8vvik","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex308","article-title":"Insulin Resistance in a Large Cohort of Women With Polycystic Ovary Syndrome: A Comparison Between Euglycaemic-Hyperinsulinaemic Clamp and Surrogate Indexes","volume":"32","author":"Tosi","year":"2017","journal-title":"Hum Reprod"},{"key":"B24","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s12958-020-00613-z","article-title":"Combined Use of Diane-35 and Metformin Improves the Ovulation in the PCOS Rat Model Possibly via Regulating Glycolysis Pathway","volume":"18","author":"Zhang","year":"2020","journal-title":"Reprod Biol Endocrinol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.732","article-title":"Genome-Wide Association Study Identifies Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21 and 9q33.3","volume":"43","author":"Chen","year":"2011","journal-title":"Nat Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2384","article-title":"Genome-Wide Association Study Identifies Eight New Risk Loci for Polycystic Ovary Syndrome","volume":"44","author":"Shi","year":"2012","journal-title":"Nat Genet"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.2011.03460.x","article-title":"Current Perspectives of Insulin Resistance and Polycystic Ovary Syndrome","volume":"28","author":"Pauli","year":"2011","journal-title":"Diabetes Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dep444","article-title":"Metformin Influence on Hormone Levels at Birth, in PCOS Mothers and Their Newborns","volume":"25","author":"Carlsen","year":"2010","journal-title":"Hum Reprod"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12339","article-title":"Glucose and Metformin Modulate Human First Trimester Trophoblast Function: A Model and Potential Therapy for Diabetes-Associated Uteroplacental Insufficiency","volume":"73","author":"Han","year":"2015","journal-title":"Am J Reprod Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmv029","article-title":"Pregnancy Complications in Women With Polycystic Ovary Syndrome","volume":"21","author":"Palomba","year":"2015","journal-title":"Hum Reprod Update"},{"key":"B31","doi-asserted-by":"publisher","first-page":"CD003053","DOI":"10.1002\/14651858.CD003053.pub6","article-title":"Insulin-Sensitising Drugs (Metformin, Rosiglitazone, Pioglitazone, D-Chiro-Inositol) for Women With Polycystic Ovary Syndrome, Oligo Amenorrhoea and Subfertility","volume":"11","author":"Morley","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dev265","article-title":"Placental Characteristics in Women With Polycystic Ovary Syndrome","volume":"30","author":"Koster","year":"2015","journal-title":"Hum Reprod"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1080\/17446651.2019.1576522","article-title":"Hyperandrogenic Origins of Polycystic Ovary Syndrome - Implications for Pathophysiology and Therapy","volume":"14","author":"Abbott","year":"2019","journal-title":"Expert Rev Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-02419","article-title":"Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age; Follow-Up of Two RCTs","volume":"103","author":"Engen Hanem","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1530\/REP-15-0352","article-title":"Letrozole vs Estradiol Valerate Induced PCOS in Rats: Glycemic, Oxidative and Inflammatory Status Assessment","volume":"151","author":"Daneasa","year":"2016","journal-title":"Reproduction"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.303.6809.1019","article-title":"Fetal and Infant Growth and Impaired Glucose Tolerance at Age 64","volume":"303","author":"Hales","year":"1991","journal-title":"BMJ"},{"key":"B37","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1530\/REP-19-0197","article-title":"Mechanisms of Intergenerational Transmission of Polycystic Ovary Syndrome","volume":"159","author":"Dumesic","year":"2020","journal-title":"Reproduction"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/372182a0","article-title":"Insulin Resistance and Growth Retardation in Mice Lacking Insulin Receptor Substrate-1","volume":"372","author":"Tamemoto","year":"1994","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27603","article-title":"Insulin Resistance: Review of the Underlying Molecular Mechanisms","volume":"234","author":"Yaribeygi","year":"2019","journal-title":"J Cell Physiol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1210\/er.18.6.774","article-title":"Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis","volume":"18","author":"Dunaif","year":"1997","journal-title":"Endocr Rev"},{"key":"B41","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.ebiom.2018.08.047","article-title":"Metformin From Mother to Unborn Child - Are There Unwarranted Effects","volume":"35","author":"Nguyen","year":"2018","journal-title":"EBioMedicine"},{"key":"B42","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1477-7827-10-36","article-title":"Association of the Genetic Variants of Luteinizing Hormone, Luteinizing Hormone Receptor and Polycystic Ovary Syndrome","volume":"10","author":"Liu","year":"2012","journal-title":"Reprod Biol Endocrinol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-1231","article-title":"Anti-Mullerian Hormone, its Receptor, FSH Receptor, and Androgen Receptor Genes are Overexpressed by Granulosa Cells From Stimulated Follicles in Women With Polycystic Ovary Syndrome","volume":"93","author":"Catteau-Jonard","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e0168870","DOI":"10.1371\/journal.pone.0168870","article-title":"Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome","volume":"12","author":"Pau","year":"2017","journal-title":"PloS One"},{"key":"B45","doi-asserted-by":"publisher","first-page":"83","DOI":"10.24425\/pjvs.2019.127075","article-title":"Estrogenic Properties of Genistein Acting on FSHR and LHR in Rats With PCOS","volume":"22","author":"Zhang","year":"2019","journal-title":"Pol J Vet Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1865","article-title":"Metformin Inhibits Follicle-Stimulating Hormone (FSH) Action in Human Granulosa Cells: Relevance to Polycystic Ovary Syndrome","volume":"98","author":"Rice","year":"2013","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.701590\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T12:48:14Z","timestamp":1628858894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.701590\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,13]]},"references-count":46,"alternative-id":["10.3389\/fendo.2021.701590"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.701590","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,13]]},"article-number":"701590"}}