{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T11:54:43Z","timestamp":1789559683788,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the framework of the Polish Ministry of Science and Higher Education\u2019s program: \u201cRegional Initiative Excellence\u201d in the years 2019\u20132022","award":["005\/RID\/2018\/19"],"award-info":[{"award-number":["005\/RID\/2018\/19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>This study aims to investigate the effects of a high-fat, high-fructose (HF\/HFr) diet on metabolic\/endocrine dysregulations associated with letrozole (LET)-induced Polycystic Ovarian Syndrome (PCOS) in prepubertal female mice. Thirty-two prepubertal C57BL\/6 mice were randomly divided into four groups of eight and implanted with LET or a placebo, with simultaneous administration of an HF\/HFr\/standard diet for five weeks. After sacrifice, the liver and blood were collected for selected biochemical analyses. The ovaries were taken for histopathological examination. The LET+HF\/HFr group gained significantly more weight than the LET-treated mice. Both the LET+HF\/HFr and the placebo-treated mice on the HF\/HFr diet developed polycystic ovaries. Moreover the LET+HF\/HFr group had significantly elevated testosterone levels, worsened lipid profile and indices of insulin sensitivity. In turn, the HF\/HFr diet alone led to similar changes in the LET-treated group, except for the indices of insulin sensitivity. Hepatic steatosis also occurred in both HF\/HFr groups. The LET-treated group did not develop endocrine or metabolic abnormalities, but polycystic ovaries were seen. Since the HF\/HFr diet can cause substantial metabolic and reproductive dysregulation in both LET-treated and placebo mice, food items rich in simple sugar\u2014particularly fructose\u2014and saturated fat, which have the potential to lead to PCOS progression, should be eliminated from the diet of young females.<\/jats:p>","DOI":"10.3390\/nu14122478","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T03:01:22Z","timestamp":1655348482000},"page":"2478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Role of a High-Fat, High-Fructose Diet on Letrozole-Induced Polycystic Ovarian Syndrome in Prepubertal Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-9120","authenticated-orcid":false,"given":"Joanna Maria","family":"Pieczy\u0144ska","sequence":"first","affiliation":[{"name":"Department of Human Nutrition and Dietetics, Pozna\u0144 University of Life Sciences, 60-637 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7182-6905","authenticated-orcid":false,"given":"Ewa","family":"Pruszy\u0144ska-Oszma\u0142ek","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology, Biochemistry and Biostructure, Pozna\u0144 University of Life Sciences, 60-637 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0715-0223","authenticated-orcid":false,"given":"Pawe\u0142 Antoni","family":"Ko\u0142odziejski","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology, Biochemistry and Biostructure, Pozna\u0144 University of Life Sciences, 60-637 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5046-7416","authenticated-orcid":false,"given":"Anna","family":"\u0141ukomska","sequence":"additional","affiliation":[{"name":"Department of Preclinical Sciences and Infectious Diseases, Pozna\u0144 University of Life Sciences, 60-637 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2268-9326","authenticated-orcid":false,"given":"Joanna","family":"Bajerska","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition and Dietetics, Pozna\u0144 University of Life Sciences, 60-637 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174746","DOI":"10.1016\/j.ejphar.2022.174746","article-title":"Role of high-fat diet on letrozole-induced polycystic ovarian syndrome in rats","volume":"917","author":"Begum","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.fertnstert.2016.05.011","article-title":"Environmental determinants of polycystic ovary syndrome","volume":"106","author":"Merkin","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Torres, P.J., Skarra, D.V., Ho, B.S., Sau, L., Anvar, A.R., Kelley, S.T., and Thackray, V.G. (2019). Letrozole treatment of adult female mice results in a similar reproductive phenotype but distinct changes in metabolism and the gut microbiome compared to pubertal mice. BMC Microbiol., 19.","DOI":"10.1186\/s12866-019-1425-7"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1210\/jc.2006-2012","article-title":"Identifying Children at Risk for Polycystic Ovary Syndrome","volume":"92","author":"Rosenfield","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/j.1471-0528.2009.02383.x","article-title":"Hyperandrogenaemia in adolescent girls: Origins of abnormal gonadotropin-releasing hormone secretion","volume":"117","author":"McCartney","year":"2010","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cca.2019.11.003","article-title":"Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity","volume":"502","author":"Zeng","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1210\/er.2015-1104","article-title":"The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited","volume":"37","author":"Rosenfield","year":"2016","journal-title":"Endocr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/obr.12472","article-title":"The barriers and enablers of healthy eating among young adults: A missing piece of the obesity puzzle: A scoping review: Barriers and enablers of healthy eating","volume":"18","author":"Munt","year":"2017","journal-title":"Obes. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"792949","DOI":"10.3389\/fmed.2022.792949","article-title":"Fructose Intake, Hypertension and Cardiometabolic Risk Factors in Children and Adolescents: From Pathophysiology to Clinical Aspects. A Narrative Review","volume":"9","author":"Giussani","year":"2022","journal-title":"Front. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"632312","DOI":"10.3389\/fnins.2021.632312","article-title":"Western Diet Consumption During Development: Setting the Stage for Neurocognitive Dysfunction","volume":"15","author":"Tsan","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.socscimed.2015.10.007","article-title":"Polycystic ovary syndrome in globalizing India: An ecosocial perspective on an emerging lifestyle disease","volume":"146","author":"Pathak","year":"2015","journal-title":"Soc. Sci. Med."},{"key":"ref_12","first-page":"E1076","article-title":"Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model","volume":"308","author":"Ressler","year":"2015","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Arroyo, P., Ho, B.S., Sau, L., Kelley, S.T., and Thackray, V.G. (2019). Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0223274"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1210\/en.2007-0168","article-title":"A New Rat Model Exhibiting Both Ovarian and Metabolic Characteristics of Polycystic Ovary Syndrome","volume":"148","author":"Manneras","year":"2007","journal-title":"Endocrinology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ryu, Y., Kim, S.W., Kim, Y.Y., and Ku, S.-Y. (2019). Animal Models for Human Polycystic Ovary Syndrome (PCOS) Focused on the Use of Indirect Hormonal Perturbations: A Review of the Literature. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112720"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.arcmed.2003.10.005","article-title":"Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease","volume":"35","author":"Kafali","year":"2004","journal-title":"Arch. Med. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1095\/biolreprod.115.131631","article-title":"A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1","volume":"93","author":"Kauffman","year":"2015","journal-title":"Biol. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, H.-B., Loh, D.H., Whittaker, D.S., Cutler, T., Howland, D., and Colwell, C.S. (2018). Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington\u2019s Disease. Eneuro, 5.","DOI":"10.1523\/ENEURO.0431-17.2017"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"838204","DOI":"10.3389\/fendo.2022.838204","article-title":"Mogroside V Improves Follicular Development and Ovulation in Young-Adult PCOS Rats Induced by Letrozole and High-Fat Diet Through Promoting Glycolysis","volume":"13","author":"Huang","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1210\/en.2013-1428","article-title":"Ovarian Cycle-Specific Regulation of Adipose Tissue Lipid Storage by Testosterone in Female Nonhuman Primates","volume":"154","author":"Varlamov","year":"2013","journal-title":"Endocrinology"},{"key":"ref_21","first-page":"E1292","article-title":"Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys","volume":"306","author":"McGee","year":"2014","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1095\/biolreprod.116.142786","article-title":"High-fat high-sugar diet induces polycystic ovary syndrome in a rodent model","volume":"96","author":"Roberts","year":"2017","journal-title":"Biol. Reprod."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1007\/s00449-020-02320-w","article-title":"Characterization on gut microbiome of PCOS rats and its further design by shifts in high-fat diet and dihydrotestosterone induction in PCOS rats","volume":"44","author":"Zheng","year":"2020","journal-title":"Bioprocess Biosyst. Eng."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., and Avey, M.T. (2020). Baker MThe ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. Boutron I, redaktor. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1093\/humrep\/deh873","article-title":"Serum anti-Mullerian hormone levels during controlled ovarian hyperstimulation in women with polycystic ovaries with and without hyperandrogenism","volume":"20","author":"Margalioth","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e923073-1","DOI":"10.12659\/MSM.923073","article-title":"Letrozole Rat Model Mimics Human Polycystic Ovarian Syndrome and Changes in Insulin Signal Pathways","volume":"26","author":"Xu","year":"2020","journal-title":"Med Sci. Monit."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12958-018-0391-5","article-title":"A novel and compact review on the role of oxidative stress in female reproduction","volume":"16","author":"Lu","year":"2018","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_29","first-page":"178","article-title":"Evaluating indicators of oxidative stress and their relationship with Insulin Resistance in polycystic ovary syndrome","volume":"21","author":"Alipour","year":"2019","journal-title":"Prog. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1210\/en.2016-1898","article-title":"Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance","volume":"158","author":"Skarra","year":"2017","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"bnaa010","DOI":"10.1210\/endrev\/bnaa010","article-title":"Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome","volume":"41","author":"Padmanabhan","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jsbmb.2009.12.010","article-title":"Insulin and hyperandrogenism in women with polycystic ovary syndrome","volume":"122","author":"Baptiste","year":"2009","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1530\/REP-17-0584","article-title":"High-fat diet exposure from pre-pubertal age induces polycystic ovary syndrome (PCOS) in rats","volume":"155","author":"Patel","year":"2018","journal-title":"Reproduction"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112894","DOI":"10.1016\/j.physbeh.2020.112894","article-title":"Sex differences in response to short-term high fat diet in mice","volume":"221","author":"Huang","year":"2020","journal-title":"Physiol. Behav."},{"key":"ref_35","first-page":"725","article-title":"The clinical characteristics and etiological study of nonalcoholic fatty liver disease in Chinese women with PCOS","volume":"11","author":"Qu","year":"2013","journal-title":"Iran. J. Reprod. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.3748\/wjg.v19.i8.1166","article-title":"Fructose as a key player in the development of fatty liver disease","volume":"19","author":"Basaranoglu","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4995","DOI":"10.3390\/nu7064995","article-title":"Hepatic Steatosis as a Marker of Metabolic Dysfunction","volume":"7","author":"Fabbrini","year":"2015","journal-title":"Nutrients"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13098-021-00647-2","article-title":"Diet-induced obesity in animal models: Points to consider and influence on metabolic markers","volume":"13","author":"Pereira","year":"2021","journal-title":"Diabetol. Metab. 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