{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T21:38:30Z","timestamp":1771882710858,"version":"3.50.1"},"reference-count":55,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is associated with reproductive problems including subfertility and early pregnancy loss. Individuals with metabolic syndrome often consume excess fructose, and several studies have concluded that excess fructose intake contributes to metabolic syndrome development. Here, we examined the effects of increased fructose consumption on pregnancy outcomes in mice. Female mice fed a high-fructose diet (HFrD) for 6 weeks developed glucose intolerance and mild fatty liver but did not develop other prominent features of metabolic syndrome such as weight gain, hyperglycemia, and hyperinsulinemia. Upon mating, HFrD-exposed mice had lower pregnancy rates and smaller litters at midgestation than chow-fed controls. To explain this phenomenon, we performed artificial decidualization experiments and found that HFrD consumption impaired decidualization. This appeared to be due to decreased circulating progesterone as exogenous progesterone administration rescued decidualization. Furthermore, HFrD intake was associated with decreased bone morphogenetic protein 2 expression and signaling, both of which were restored by exogenous progesterone. Finally, expression of forkhead box O1 and superoxide dismutase 2 [Mn] proteins were decreased in the uteri of HFrD-fed mice, suggesting that HFrD consumption promotes a prooxidative environment in the endometrium. In summary, these data suggest that excess fructose consumption impairs murine fertility by decreasing steroid hormone synthesis and promoting an adverse uterine environment.<\/jats:p>","DOI":"10.1210\/en.2015-1618","type":"journal-article","created":{"date-parts":[[2015,12,17]],"date-time":"2015-12-17T16:56:50Z","timestamp":1450371410000},"page":"956-968","source":"Crossref","is-referenced-by-count":27,"title":["Excess Maternal Fructose Consumption Increases Fetal Loss and Impairs Endometrial Decidualization in Mice"],"prefix":"10.1210","volume":"157","author":[{"given":"Jessica L.","family":"Saben","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeenat","family":"Asghar","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie S.","family":"Rhee","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Drury","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne","family":"Scheaffer","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelle H.","family":"Moley","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2015,12,17]]},"reference":[{"key":"2020071612254513500_B1","first-page":"1","article-title":"Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003\u20132006","author":"Ervin","year":"2009","journal-title":"Natl Health Stat Report"},{"key":"2020071612254513500_B2","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1301\/nr.2007.jun.S13-S23","article-title":"Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms","volume":"65","author":"Rutledge","year":"2007","journal-title":"Nutr Rev"},{"key":"2020071612254513500_B3","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1113\/jphysiol.2011.215731","article-title":"The role of fructose transporters in diseases linked to excessive fructose intake","volume":"591","author":"Douard","year":"2013","journal-title":"J Physiol"},{"key":"2020071612254513500_B4","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.2337\/db12-1814","article-title":"Sugar, uric acid, and the etiology of diabetes and obesity","volume":"62","author":"Johnson","year":"2013","journal-title":"Diabetes"},{"key":"2020071612254513500_B5","doi-asserted-by":"crossref","first-page":"F625","DOI":"10.1152\/ajprenal.00140.2005","article-title":"A causal role for uric acid in fructose-induced metabolic syndrome","volume":"290","author":"Nakagawa","year":"2006","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020071612254513500_B6","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1080\/15257770802138558","article-title":"Uric acid: the oxidant-antioxidant paradox","volume":"27","author":"Sautin","year":"2008","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"2020071612254513500_B7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.fertnstert.2014.05.005","article-title":"Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss","volume":"102","author":"Boots","year":"2014","journal-title":"Fertil Steril"},{"key":"2020071612254513500_B8","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ajog.2003.10.704","article-title":"Impact of obesity on spontaneous abortion","volume":"190","author":"Bellver","year":"2004","journal-title":"Am J Obstet Gynecol"},{"key":"2020071612254513500_B9","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.metabol.2012.08.012","article-title":"The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review","volume":"62","author":"Michalakis","year":"2013","journal-title":"Metabolism"},{"key":"2020071612254513500_B10","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.fertnstert.2008.12.032","article-title":"Female obesity impairs in vitro fertilization outcome without affecting embryo quality","volume":"93","author":"Bellver","year":"2010","journal-title":"Fertil Steril"},{"key":"2020071612254513500_B11","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.fertnstert.2012.04.004","article-title":"The effect of body mass index on the outcomes of first assisted reproductive technology cycles","volume":"98","author":"Moragianni","year":"2012","journal-title":"Fertil Steril"},{"key":"2020071612254513500_B12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1055\/s-0029-1242989","article-title":"Endometrial decidualization: of mice and men","volume":"28","author":"Ramathal","year":"2010","journal-title":"Semin Reprod Med"},{"key":"2020071612254513500_B13","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1023\/A:1015411113468","article-title":"Preeclampsia, an implantation disorder","volume":"3","author":"Waite","year":"2002","journal-title":"Rev Endocr Metab Disord"},{"key":"2020071612254513500_B14","first-page":"101","article-title":"Defective implantation and placentation: laying the blueprint for pregnancy complications","author":"Norwitz","journal-title":"Reprod Biomed"},{"key":"2020071612254513500_B15","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1055\/s-2007-991037","article-title":"Physiology and pathology of implantation in the human and nonhuman primate","volume":"25","author":"Fazleabas","year":"2007","journal-title":"Semin Reprod Med"},{"key":"2020071612254513500_B16","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1093\/humupd\/dmq037","article-title":"Implantation failure: molecular mechanisms and clinical treatment","volume":"17","author":"Cakmak","year":"2011","journal-title":"Hum Reprod Update"},{"key":"2020071612254513500_B17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1055\/s-0031-1293203","article-title":"Clinical assessment and management of the endometrium in recurrent early pregnancy loss","volume":"29","author":"Patel","year":"2011","journal-title":"Semin Reprod Med"},{"key":"2020071612254513500_B18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00795-013-0018-z","article-title":"The role of FOXO1 in the decidual transformation of the endometrium and early pregnancy","volume":"46","author":"Kajihara","year":"2013","journal-title":"Med Mol Morphol"},{"key":"2020071612254513500_B19","doi-asserted-by":"crossref","first-page":"10989","DOI":"10.1074\/jbc.M113.527002","article-title":"Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis","volume":"289","author":"Debosch","year":"2014","journal-title":"J Biol Chem"},{"key":"2020071612254513500_B20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1095\/biolreprod.113.113217","article-title":"The fatty acid beta-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice","volume":"90","author":"Tsai","year":"2014","journal-title":"Biol Reprod"},{"key":"2020071612254513500_B21","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1530\/REP-08-0167","article-title":"Paternal effect on embryo quality in diabetic mice is related to poor sperm quality and associated with decreased glucose transporter expression","volume":"136","author":"Kim","year":"2008","journal-title":"Reprod Suppl"},{"key":"2020071612254513500_B22","doi-asserted-by":"crossref","first-page":"e98066","DOI":"10.1371\/journal.pone.0098066","article-title":"Maternal obesity reduces milk lipid production in lactating mice by inhibiting acetyl-CoA carboxylase and impairing fatty acid synthesis","volume":"9","author":"Saben","year":"2014","journal-title":"PLoS One"},{"key":"2020071612254513500_B23","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/humrep\/deg255","article-title":"Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium","volume":"18","author":"Brenner","year":"2003","journal-title":"Hum Reprod"},{"key":"2020071612254513500_B24","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1128\/MCB.00342-07","article-title":"Bmp2 is critical for the murine uterine decidual response","volume":"27","author":"Lee","year":"2007","journal-title":"Mol Cell Biol"},{"key":"2020071612254513500_B25","doi-asserted-by":"crossref","first-page":"31725","DOI":"10.1074\/jbc.M704723200","article-title":"Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human","volume":"282","author":"Li","year":"2007","journal-title":"J Biol Chem"},{"key":"2020071612254513500_B26","doi-asserted-by":"crossref","first-page":"40732","DOI":"10.1074\/jbc.M112.399899","article-title":"Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver","volume":"287","author":"Lanaspa","year":"2012","journal-title":"J Biol Chem"},{"key":"2020071612254513500_B27","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1210\/me.2006-0118","article-title":"Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization","volume":"20","author":"Kajihara","year":"2006","journal-title":"Mol Endocrinol"},{"key":"2020071612254513500_B28","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1210\/en.2012-1585","article-title":"WNT4 acts downstream of BMP2 and functions via \u03b2-catenin signaling pathway to regulate human endometrial stromal cell differentiation","volume":"154","author":"Li","year":"2013","journal-title":"Endocrinology"},{"key":"2020071612254513500_B29","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1038\/onc.2008.27","article-title":"FOXO animal models reveal a variety of diverse roles for FOXO transcription factors","volume":"27","author":"Arden","year":"2008","journal-title":"Oncogene"},{"key":"2020071612254513500_B30","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.jacc.2014.02.529","article-title":"Pre-eclampsia and future cardiovascular risk among women: a review","volume":"63","author":"Ahmed","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2020071612254513500_B31","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/ejcn.2012.61","article-title":"Maternal sugar consumption and risk of preeclampsia in nulliparous Norwegian women","volume":"66","author":"Borgen","year":"2012","journal-title":"Eur J Clin Nutr"},{"key":"2020071612254513500_B32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.tem.2010.12.002","article-title":"Metabolic syndrome and oocyte quality","volume":"22","author":"Cardozo","year":"2011","journal-title":"Trends Endocrinol Metab"},{"key":"2020071612254513500_B33","doi-asserted-by":"crossref","first-page":"203474","DOI":"10.1155\/2014\/203474","article-title":"Early life exposure to fructose and offspring phenotype: implications for long term metabolic homeostasis","volume":"2014","author":"Sloboda","year":"2014","journal-title":"J Obes"},{"key":"2020071612254513500_B34","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1093\/jn\/123.12.2158","article-title":"Low dose fructose ingestion during gestation and lactation affects carbohydrate metabolism in rat dams and their offspring","volume":"123","author":"Rawana","year":"1993","journal-title":"J Nutr"},{"key":"2020071612254513500_B35","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.nutres.2012.06.012","article-title":"Fructose consumption during pregnancy and lactation induces fatty liver and glucose intolerance in rats","volume":"32","author":"Zou","year":"2012","journal-title":"Nutr Res"},{"key":"2020071612254513500_B36","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1210\/en.2010-1093","article-title":"Maternal fructose intake during pregnancy and lactation alters placental growth and leads to sex-specific changes in fetal and neonatal endocrine function","volume":"152","author":"Vickers","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612254513500_B37","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1093\/jn\/121.12.1999","article-title":"Fructose and sucrose feeding during pregnancy and lactation in rats changes maternal and pup fuel metabolism","volume":"121","author":"Jen","year":"1991","journal-title":"J Nutr"},{"key":"2020071612254513500_B38","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12020-012-9815-8","article-title":"Fructose intake during pregnancy up-regulates the expression of maternal and fetal hepatic sterol regulatory element-binding protein-1c in rats","volume":"44","author":"Mukai","year":"2013","journal-title":"Endocrine"},{"key":"2020071612254513500_B39","doi-asserted-by":"crossref","first-page":"F625","DOI":"10.1152\/ajprenal.00140.2005","article-title":"A causal role for uric acid in fructose-induced metabolic syndrome","volume":"290","author":"Nakagawa","year":"2006","journal-title":"American journal of physiology Renal Physiol"},{"key":"2020071612254513500_B40","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1681\/ASN.2007040416","article-title":"Thiazide diuretics exacerbate fructose-induced metabolic syndrome","volume":"18","author":"Reungjui","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"2020071612254513500_B41","doi-asserted-by":"crossref","first-page":"757913","DOI":"10.5402\/2012\/757913","article-title":"Oral metformin treatment prevents enhanced insulin demand and placental dysfunction in the pregnant rat fed a fructose-rich diet","volume":"2012","author":"Alzamendi","year":"2012","journal-title":"ISRN Endocrinol"},{"key":"2020071612254513500_B42","doi-asserted-by":"crossref","first-page":"5310","DOI":"10.1210\/endo.140.11.7148","article-title":"Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse","volume":"140","author":"Tan","year":"1999","journal-title":"Endocrinology"},{"key":"2020071612254513500_B43","doi-asserted-by":"crossref","first-page":"11408","DOI":"10.1073\/pnas.88.24.11408","article-title":"Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation","volume":"88","author":"Bhatt","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612254513500_B44","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1101\/gad.9.18.2266","article-title":"Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities","volume":"9","author":"Lydon","year":"1995","journal-title":"Genes Dev"},{"key":"2020071612254513500_B45","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1095\/biolreprod60.5.1158","article-title":"Progesterone via its receptor antagonizes the pro-inflammatory activity of estrogen in the mouse uterus","volume":"60","author":"Tibbetts","year":"1999","journal-title":"Biol Reprod"},{"key":"2020071612254513500_B46","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.mce.2011.10.028","article-title":"The progesterone receptor regulates implantation, decidualization, and glandular development via a complex paracrine signaling network","volume":"357","author":"Wetendorf","year":"2012","journal-title":"Mol Cell Endocrinol"},{"key":"2020071612254513500_B47","doi-asserted-by":"crossref","first-page":"e0124756","DOI":"10.1371\/journal.pone.0124756","article-title":"A suppressive antagonism evidences progesterone and estrogen receptor pathway interaction with concomitant regulation of Hand2, Bmp2 and ERK during early decidualization","volume":"10","author":"Mestre-Citrinovitz","year":"2015","journal-title":"PLoS One"},{"key":"2020071612254513500_B48","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1073\/pnas.98.3.1047","article-title":"Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors","volume":"98","author":"Paria","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612254513500_B49","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jsgi.2004.03.003","article-title":"Placental oxidative stress: from miscarriage to preeclampsia","volume":"11","author":"Burton","year":"2004","journal-title":"J Soc Gynecol Investig"},{"key":"2020071612254513500_B50","doi-asserted-by":"crossref","first-page":"9179","DOI":"10.1007\/s11033-012-1790-x","article-title":"Endoplasmic reticulum stress induced by oxidative stress in decidual cells: a possible mechanism of early pregnancy loss","volume":"39","author":"Gao","year":"2012","journal-title":"Mol Biol Rep"},{"key":"2020071612254513500_B51","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1038\/nm.2498","article-title":"Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure","volume":"17","author":"Salker","year":"2011","journal-title":"Nat Med"},{"key":"2020071612254513500_B52","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1677\/joe.1.06451","article-title":"Forkhead transcription factor FOXO1A is critical for induction of human decidualization","volume":"189","author":"Grinius","year":"2006","journal-title":"J Endocrinol"},{"key":"2020071612254513500_B53","doi-asserted-by":"crossref","first-page":"3870","DOI":"10.1210\/en.2006-0167","article-title":"FOXO1A differentially regulates genes of decidualization","volume":"147","author":"Buzzio","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612254513500_B54","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1210\/me.2007-0058","article-title":"Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells","volume":"21","author":"Takano","year":"2007","journal-title":"Mol Endocrinol"},{"key":"2020071612254513500_B55","doi-asserted-by":"crossref","first-page":"e6845","DOI":"10.1371\/journal.pone.0006845","article-title":"HoxA-11 and FOXO1A cooperate to regulate decidual prolactin expression: towards inferring the core transcriptional regulators of decidual genes","volume":"4","author":"Lynch","year":"2009","journal-title":"PLoS One"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/157\/2\/956\/9000944\/endo0956.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/157\/2\/956\/9000944\/endo0956.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T20:51:17Z","timestamp":1748724677000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/157\/2\/956\/2423106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,17]]},"references-count":55,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2015-1618","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,17]]}}}