{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:00:49Z","timestamp":1792620049325,"version":"4.5.0"},"reference-count":69,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T00:00:00Z","timestamp":1543881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004595","name":"Universiti Sains Malaysia","doi-asserted-by":"publisher","award":["RUI: 1001\/PPSP\/8012251"],"award-info":[{"award-number":["RUI: 1001\/PPSP\/8012251"]}],"id":[{"id":"10.13039\/501100004595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Metformin has long been used for glycemic control in diabetic state. Recently, other benefits of metformin beyond blood glucose regulation have emerged.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To investigate the effect of metformin on the expression of testicular steroidogenesis\u2010related genes, spermatogenesis, and fertility of male diabetic rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Eighteen adult male <jats:italic>Sprague Dawley<\/jats:italic> rats were divided into three groups, namely normal control (NC), diabetic control (DC), and metformin\u2010treated (300\u00a0mg\/kg body weight\/day) diabetic rats (D+Met). Diabetes was induced using a single intraperitoneal injection of streptozotocin (60\u00a0mg\/kg b.w.), followed by oral treatment with metformin for four weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Diabetes decreased serum and intratesticular testosterone levels and increased serum but not intratesticular levels of luteinizing hormone. Sperm count, motility, viability, and normal morphology were decreased, while sperm nuclear DNA fragmentation was increased in DC group, relative to NC group. Testicular mRNA levels of androgen receptor, luteinizing hormone receptor, cytochrome P450 enzyme (CYP11A1), steroidogenic acute regulatory (StAR) protein, 3\u03b2\u2010hydroxysteroid dehydrogenase (HSD), and 17\u03b2\u2010HSD, as well as the level of StAR protein and activities of CYP11A1, 3\u03b2\u2010HSD, and 17\u03b2\u2010HSD, were decreased in DC group. Similarly, decreased activities of epididymal antioxidant enzymes and increased lipid peroxidation were observed in DC group. Consequently, decreased litter size, fetal weight, mating and fertility indices, and increased pre\u2010 and post\u2010implantation losses were recorded in DC group. Following intervention with metformin, we observed increases in serum and intratesticular testosterone levels, Leydig cell count, improved sperm parameters, and decreased sperm nuclear DNA fragmentation. Furthermore, mRNA levels and activities of steroidogenesis\u2010related enzymes were increased, with improved fertility outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and conclusion<\/jats:title><jats:p>Diabetes mellitus is associated with dysregulation of steroidogenesis, abnormal spermatogenesis, and fertility decline. Controlling hyperglycemia is therefore crucial in preserving male reproductive function. Metformin not only regulates blood glucose level, but also preserves male fertility in diabetic state.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.12567","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T04:04:45Z","timestamp":1543982685000},"page":"110-123","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Down\u2010regulation of steroidogenesis\u2010related genes and its accompanying fertility decline in streptozotocin\u2010induced diabetic male rats: ameliorative effect of metformin"],"prefix":"10.1111","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-9468","authenticated-orcid":false,"given":"V. U.","family":"Nna","sequence":"first","affiliation":[{"name":"Department of Physiology School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Malaysia"},{"name":"Department of Physiology Faculty of Basic Medical Sciences College of Medical Sciences University of Calabar Calabar Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6845-8670","authenticated-orcid":false,"given":"A. B. A.","family":"Bakar","sequence":"additional","affiliation":[{"name":"Department of Physiology School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1393-5775","authenticated-orcid":false,"given":"A.","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Basic Science and Oral Biology Unit School of Dental Sciences Universiti Sains Malaysia Kubang Kerian Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9333-1957","authenticated-orcid":false,"given":"M.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Physiology School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Malaysia"},{"name":"Unit of Integrative Medicine School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064751"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.01.011"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1681\/ASN.V12122747","article-title":"Oxidative stress and endothelial function in chronic renal failure","volume":"12","author":"Annuk M","year":"2001","journal-title":"J Am Soc Nephrol"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0102374"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0102-865020160060000008"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.5603\/FHC.a2015.0005"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1939-4640.2004.tb02845.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.14260\/Jemds\/2017\/405"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","unstructured":"BremerAA&MillerWL(2014)Regulation of steroidogenesis. In: Cellular Endocrinology in Health and Disease (edsUlloa\u2010AguirreA&ConnPM) 2014 pp.207\u2013227.Elsevier Inc. USA.","DOI":"10.1016\/B978-0-12-408134-5.00013-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/608512"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00212.x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2016.10.079"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2018.02.023"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-1649"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.03.072"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2016.12.021"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.12846"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deh263"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(00)01666-6"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0042-101549"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)42083-8"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bju.13516"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12399"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3109\/13813455.2010.486405"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-1280"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2014.12.010"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.07.026"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2011.11.051"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1439-0272.2011.01178.x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.54.5.356"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.7421"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.jfas.2016.04.012"},{"key":"e_1_2_9_34_1","first-page":"799.710","article-title":"The improvement of exercise training on diabetes\u2010damaged cAMP and steroidogenesis pathway in Leydig cells of streptozotocin\u2010induced diabetes rat","volume":"31","author":"Lin TW","year":"2017","journal-title":"FASEB J"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.12454"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2008.11.006"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2011.11.012"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3896\/IBRA.4.03.1.03"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms12095508"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/0748233711432568"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-014-3521-0"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2012.02.085"},{"key":"e_1_2_9_43_1","first-page":"1013","article-title":"Honey and metformin ameliorated diabetes\u2010induced damages in testes of rat; correlation with hormonal changes","volume":"11","author":"Nasrolahi O","year":"2013","journal-title":"Iranian J Reprod Med"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.12669"},{"key":"e_1_2_9_45_1","first-page":"233","article-title":"Diabetes mellitus\u2010induced male reproductive impairment: the role of natural products: a review","volume":"7","author":"Nna VU","year":"2017","journal-title":"J Appl Pharmaceut Sci"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2017.07.087"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2018.07.028"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2017.03.024"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-12-3"},{"key":"e_1_2_9_50_1","first-page":"49","article-title":"Quantitative evaluation of Leydig cell number and steroidogenesis in tandem with spermatogenic macro\u2010parameters following experimentally induced diabetes mellitus and obesity in rat","volume":"48","author":"Pavlova E","year":"2016","journal-title":"Scripta Scientifica Medica"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-2190"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.12481"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(01)01423-0"},{"key":"e_1_2_9_54_1","first-page":"3","article-title":"Role of pioglitazone with metformin or glimepiride on oxidative stress\u2010induced nuclear damage and reproductive toxicity in diabetic rats","volume":"17","author":"Rabbani SI","year":"2010","journal-title":"Malaysian J Med Sci"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.11.007"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6TX00099A"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.03.029"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2015.11.006"},{"key":"e_1_2_9_59_1","first-page":"301","article-title":"Metformin\u2010induced regulation of the intestinal D\u2010glucose transporters","volume":"61","author":"Sakar Y","year":"2010","journal-title":"J Physiol Pharmacol"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-016-0893-y"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1527"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ16-0430"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.5603\/FHC.a2015.0006"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003053.pub6"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/des264"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.2164\/jandrol.111.013193"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2014.04.005"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.05.067"},{"key":"e_1_2_9_69_1","doi-asserted-by":"crossref","unstructured":"YangJ LinS ZhangY WuG YangQ LvQ&HuJ. (2017)Taurine improves sexual function in streptozotocin\u2010induced diabetic rats. In:Taurine 10: Advances in Experimental Medicine and Biology(edsLeeDH SchafferSW ParkE KimHW) vol 975 pp.307\u2013318.Springer Dordrecht Netherlands.","DOI":"10.1007\/978-94-024-1079-2_27"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13505"}],"container-title":["Andrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fandr.12567","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/andr.12567","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/andr.12567","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/andr.12567","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T18:00:08Z","timestamp":1694368808000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/andr.12567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,4]]},"references-count":69,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,1]]}},"alternative-id":["10.1111\/andr.12567"],"URL":"https:\/\/doi.org\/10.1111\/andr.12567","archive":["Portico"],"relation":{},"ISSN":["2047-2919","2047-2927"],"issn-type":[{"value":"2047-2919","type":"print"},{"value":"2047-2927","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,4]]},"assertion":[{"value":"2018-09-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}