{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:46:22Z","timestamp":1759970782131,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Consejo Nacional de Humanidades","award":["257549","39211","322333"],"award-info":[{"award-number":["257549","39211","322333"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Objective: To determine the impact of hypothyroidism on uterine glycogen accumulation during pregnancy. Methods: Non-pregnant and pregnant (days 5, 10, and 20) rabbits were grouped into control and methimazole (MMI) groups. In rabbits, serum concentrations of thyroxine (T4), triiodothyronine, glucose, insulin, progesterone, and estradiol were quantified. In uterine inter- and implantation sites, the glycogen content and expression of lactate dehydrogenase (LDH), GLUT4, and aromatase were quantified via Western blot. Fetuses\u2019 characteristics at 20 days of pregnancy were analyzed. Two-way ANOVA was used to compare variables between groups. Results: Pregnancy reduced T4 concentrations but not T3. In virgin groups, MMI treatment significantly reduced the concentrations of T4 and T3 and increased the expression of GLUT4 and aromatase in the uterus compared to the control group. In pregnant groups, T4, T3, glucose, insulin, progesterone, and estradiol levels were similar between control and MMI-treated rabbits. Compared to controls, MMI treatment in pregnant rabbits (a) reduced GLUT4 expression on inter-implantation sites on day 5; (b) increased glycogen content on implantation sites but reduced GLUT4 expression on inter-and implantation sites on day 10; (c) increased glycogen content and LDH and aromatase expression but reduced GLUT4 on inter-implantation sites; and (d) increased glycogen content and the expression of LDH, GLUT4, and aromatase on day 20 on implantation sites. Moreover, the fetus characteristics were similar between groups. Conclusions: MMI-induced hypothyroidism is associated with changes in the uterine content of glycogen and the expression of LDH, GLUT4, and aromatase during pregnancy.<\/jats:p>","DOI":"10.3390\/metabo15020082","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T11:42:37Z","timestamp":1738237357000},"page":"82","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Methimazole-Induced Hypothyroidism Increases the Content of Glycogen and Changes the Expression of LDH, GLUT4, and Aromatase in the Pregnant Uterus of Rabbits"],"prefix":"10.3390","volume":"15","author":[{"given":"Marlen","family":"Espindola-Lozano","sequence":"first","affiliation":[{"name":"Ph.D. Program in Biological Sciences, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maribel","family":"M\u00e9ndez-Tepepa","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Biological Sciences, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlenne","family":"Castillo-Romano","sequence":"additional","affiliation":[{"name":"Master Program in Biological Sciences, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7818-9208","authenticated-orcid":false,"given":"Rubicela","family":"Rojas-Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Biological Sciences, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5022-2339","authenticated-orcid":false,"given":"Leticia","family":"Nicol\u00e1s-Toledo","sequence":"additional","affiliation":[{"name":"Center Tlaxcala of Behavior Biology, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Rodr\u00edguez-Antol\u00edn","sequence":"additional","affiliation":[{"name":"Center Tlaxcala of Behavior Biology, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-3335","authenticated-orcid":false,"given":"Francisco","family":"Castel\u00e1n","sequence":"additional","affiliation":[{"name":"Center Tlaxcala of Behavior Biology, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"},{"name":"Department of Cellular and Physiology, Institute of Biomedical Research, Autonomous Nacional University of Mexico, CP 04510 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3960-2351","authenticated-orcid":false,"given":"Estela","family":"Cuevas-Romero","sequence":"additional","affiliation":[{"name":"Center Tlaxcala of Behavior Biology, Autonomous University of Tlaxcala, 90070 Tlaxcala, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.lfs.2019.05.063","article-title":"Hypothyroidism Induces Uterine Hyperplasia and Inflammation Related to Sex Hormone Receptors Expression in Virgin Rabbits","volume":"230","year":"2019","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Brown, E.D.L., Obeng-Gyasi, B., Hall, J.E., and Shekhar, S. (2023). The Thyroid Hormone Axis and Female Reproduction. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129815"},{"key":"ref_3","first-page":"818","article-title":"Hypothyroidism Alters the Uterine Lipid Levels in Pregnant Rabbits and Affects the Fetal Size","volume":"19","author":"Berbel","year":"2018","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_4","first-page":"135","article-title":"Low Birth Weight in Children Born to Mothers with Hyperthyroidism and High Birth Weight in Hypothyroidism, Whereas Preterm Birth Is Common in Both Conditions: A Danish National Hospital Register Study","volume":"2","author":"Andersen","year":"2013","journal-title":"Eur. Thyroid J."},{"key":"ref_5","first-page":"e34824","article-title":"A Narrative Review on the Effect of Maternal Hypothyroidism on Fetal Development","volume":"15","author":"Pande","year":"2023","journal-title":"Cureus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1071\/RD11219","article-title":"Fetal Growth Restriction in Hypothyroidism Is Associated with Changes in Proliferative Activity, Apoptosis and Vascularisation of the Placenta","volume":"24","author":"Serakides","year":"2012","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1093\/humupd\/dmu028","article-title":"Molecular Basis of Thyrotropin and Thyroid Hormone Action during Implantation and Early Development","volume":"20","author":"Colicchia","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1530\/jrf.0.0930245","article-title":"Energy Metabolism in Late Preimplantation Rat Embryos","volume":"93","author":"Brison","year":"1991","journal-title":"J. Reprod. Fertil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/mrd.23634","article-title":"Endometrial Glycogen Metabolism during Early Pregnancy in Mice","volume":"89","author":"Chen","year":"2022","journal-title":"Mol. Reprod. Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1095\/biolreprod25.1.162","article-title":"Uterine Size and Glycogen Content in Cycling and Pregnant Rats: Influence of Relaxin","volume":"25","author":"Vasilenko","year":"1981","journal-title":"Biol. Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21280","DOI":"10.1074\/jbc.M115.656629","article-title":"Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy","volume":"290","author":"Zuo","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Vrhovac Maduni\u0107, I., Karin-Kujund\u017ei\u0107, V., Maduni\u0107, J., \u0160ola, I.M., and \u0160erman, L. (2021). Endometrial Glucose Transporters in Health and Disease. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.703671"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Long, Y., Wang, Y.C., Yuan, D.Z., Dai, X.H., Liao, L.C., Zhang, X.Q., Zhang, L.X., Ma, Y.D., Lei, Y., and Cui, Z.H. (2021). GLUT4 in Mouse Endometrial Epithelium: Roles in Embryonic Development and Implantation. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.674924"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/bies.201400155","article-title":"Lactate Production by the Mammalian Blastocyst: Manipulating the Microenvironment for Uterine Implantation and Invasion?","volume":"37","author":"Gardner","year":"2015","journal-title":"Bioessays"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.rbmo.2021.09.012","article-title":"A Microenvironment of High Lactate and Low PH Created by the Blastocyst Promotes Endometrial Receptivity and Implantation","volume":"44","author":"Gurner","year":"2022","journal-title":"Reprod. Biomed. Online"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"60.e1","DOI":"10.1016\/j.ajog.2016.09.072","article-title":"Lactate Produced during Labor Modulates Uterine Inflammation via GPR81 (HCA1)","volume":"216","author":"Madaan","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.jri.2011.02.005","article-title":"Endometrial Secretions: Creating a Stimulatory Microenvironment within the Human Early Placenta and Implications for the Aetiopathogenesis of Preeclampsia","volume":"89","author":"Burton","year":"2011","journal-title":"J. Reprod. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151508","DOI":"10.1016\/j.aanat.2020.151508","article-title":"Stereological Study of the Placental Structure in Abortion-Prone Mice Model (CBA\/J\u00d7DBA\/2J)","volume":"230","author":"Hosseini","year":"2020","journal-title":"Ann. Anat."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Santos, B.R., dos Anjos Cordeiro, J.M., Santos, L.C., Barbosa, E.M., Mendon\u00e7a, L.D., Santos, E.O., de Macedo, I.O., de Lavor, M.S.L., Szawka, R.E., and Serakides, R. (2022). Kisspeptin Treatment Improves Fetal-Placental Development and Blocks Placental Oxidative Damage Caused by Maternal Hypothyroidism in an Experimental Rat Model. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.908240"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/asj.12564","article-title":"Estradiol Stimulates Glycogen Synthesis Whereas Progesterone Promotes Glycogen Catabolism in the Uterus of the American Mink (Neovison Vison)","volume":"88","author":"Bowman","year":"2017","journal-title":"Anim. Sci. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.theriogenology.2019.02.023","article-title":"Glycogen Metabolism in Mink Uterine Epithelial Cells and Its Regulation by Estradiol, Progesterone and Insulin","volume":"130","author":"Hodonu","year":"2019","journal-title":"Theriogenology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1210\/endo-110-5-1773","article-title":"Effects of Thyroid Hormone on some Uterine Responses to Estrogen","volume":"110","author":"Steinsapir","year":"1982","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1210\/endo-103-4-1164","article-title":"Regulation of the Uterine Response to Estrogen by Thyroid Hormone","volume":"103","author":"Gardners","year":"1978","journal-title":"Endocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kowalczyk-Zieba, I., Staszkiewicz-Chodor, J., Boruszewska, D., Lukaszuk, K., Jaworska, J., and Woclawek-Potocka, I. (2021). Hypothyroidism Affects Uterine Function via the Modulation of Prostaglandin Signaling. Animals, 11.","DOI":"10.3390\/ani11092636"},{"key":"ref_25","first-page":"1077","article-title":"Investigation of the Endometrial Receptivity Status in Experimental Hypothyroid-Induced Female Rats","volume":"25","author":"Gedikli","year":"2022","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/REP-12-0091","article-title":"Rabbit as a Reproductive Model for Human Health","volume":"144","author":"Fischer","year":"2012","journal-title":"Reproduction"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00418-002-0471-6","article-title":"Functional and Structural Regression of the Rabbit Corpus Luteum Is Associated with Altered Luteal Immune Cell Phenotypes and Cytokine Expression Patterns","volume":"118","author":"Krusche","year":"2002","journal-title":"Histochem. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chavatte-Palmer, P., Tarrade, A., and Rousseau-Ralliard, D. (2016). Diet before and during Pregnancy and Offspring Health: The Importance of Animal Models and What Can Be Learned from Them. Int. J. Environ. Res. Public Health, 13.","DOI":"10.3390\/ijerph13060586"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/rda.12455","article-title":"Hypothyroidism Affects Differentially the Cell Size of Epithelial Cells among Oviductal Regions of Rabbits","volume":"50","author":"Cuevas","year":"2015","journal-title":"Reprod. Domest. Anim."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.7861\/clinmed.2023-0018","article-title":"Thyroid Disease in Pregnancy","volume":"23","author":"Yap","year":"2023","journal-title":"Clin. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"bqab231","DOI":"10.1210\/endocr\/bqab231","article-title":"Maternal Hypothyroidism in Rats Reduces Placental Lactogen, Lowers Insulin Levels, and Causes Glucose Intolerance","volume":"163","author":"Kent","year":"2022","journal-title":"Endocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"bvab028","DOI":"10.1210\/jendso\/bvab028","article-title":"Subclinical Hypothyroidism Represents Visceral Adipose Indices, Especially in Women With Cardiovascular Risk","volume":"5","author":"Tsou","year":"2021","journal-title":"J. Endocr. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s12020-014-0418-4","article-title":"The Langerhans Islet Cells of Female Rabbits Are Differentially Affected by Hypothyroidism Depending on the Islet Size","volume":"48","author":"Morimoto","year":"2015","journal-title":"Endocrine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1677\/joe.0.1760247","article-title":"Maternal Hypothyroidism in the Rat Influences Placental and Liver Glycogen Stores: Fetal Growth Retardation near Term Is Unrelated to Maternal and Placental Glucose Metabolic Compromise","volume":"176","author":"Pickard","year":"2003","journal-title":"J. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1095\/biolreprod65.5.1364","article-title":"Glucose Transporter Expression in Rat Embryo and Uterus during Decidualization, Implantation, and Early Postimplantation","volume":"65","author":"Korgun","year":"2001","journal-title":"Biol. Reprod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bbacli.2015.08.004","article-title":"Lack of Cyclical Fluctuations of Endometrial GLUT4 Expression in Women with Polycystic Ovary Syndrome: Evidence for Direct Regulation of GLUT4 by Steroid Hormones","volume":"4","author":"Cui","year":"2015","journal-title":"BBA Clin."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1210\/en.2007-0665","article-title":"Inflammatory Status Influences Aromatase and Steroid Receptor Expression in Endometriosis","volume":"149","author":"Bukulmez","year":"2008","journal-title":"Endocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.2478\/v10039-012-0055-1","article-title":"Expression of Estrogen Receptors (\u03b1, \u03b2), Cyclooxygenase-2 and Aromatase in Normal Endometrium and Endometrioid Cancer of Uterus","volume":"58","author":"Knapp","year":"2013","journal-title":"Adv. Med. Sci."},{"key":"ref_39","first-page":"965","article-title":"Effect of TNF-Alpha on Endometrial Glucose Transporter-4 Expression in Patients with Polycystic Ovary Syndrome through Nuclear Factor-Kappa B Signaling Pathway Activation","volume":"72","author":"Ha","year":"2021","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/j.1460-9568.2005.04243.x","article-title":"Transient Maternal Hypothyroxinemia at Onset of Corticogenesis Alters Tangential Migration of Medial Ganglionic Eminence-Derived Neurons","volume":"22","author":"Cuevas","year":"2005","journal-title":"Eur. J. Neurosci."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/2\/82\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:39:03Z","timestamp":1759919943000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/2\/82"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,30]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["metabo15020082"],"URL":"https:\/\/doi.org\/10.3390\/metabo15020082","relation":{},"ISSN":["2218-1989"],"issn-type":[{"type":"electronic","value":"2218-1989"}],"subject":[],"published":{"date-parts":[[2025,1,30]]}}}