{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:00:10Z","timestamp":1790017210644,"version":"4.0.1"},"reference-count":41,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS)","doi-asserted-by":"publisher","award":["25660095"],"award-info":[{"award-number":["25660095"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Late-onset hypogonadism, a male age-related syndrome characterized by a decline in testosterone production in the testes, is commonly treated with testosterone replacement therapy, which has adverse side effects. Therefore, an alternative treatment is highly sought. Supplementation of a high dosage of biotin, a water-soluble vitamin that functions as a coenzyme for carboxylases involved in carbohydrate, lipid, and amino acid metabolism, has been shown to influence testis functions. However, the involvement of biotin in testis steroidogenesis has not been well clarified. In this study, we examined the effect of biotin on testosterone levels in mice and testis-derived cells. In mice, intraperitoneal treatment with biotin (1.5 mg\/kg body weight) enhanced testosterone levels in the serum and testes, without elevating serum levels of pituitary luteinizing hormone. To investigate the mechanism in which biotin increased the testosterone level, mice testis-derived I-10 cells were used. The cells treated with biotin increased testosterone production in a dose- and time-dependent manner. Biotin treatment elevated intracellular cyclic adenosine monophosphate levels via adenylate cyclase activation, followed by the activation of protein kinase A and testosterone production. These results suggest that biotin may have the potential to improve age-related male syndromes associated with declining testosterone production.<\/jats:p>","DOI":"10.3390\/nu14224761","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T21:33:02Z","timestamp":1668115982000},"page":"4761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Biotin Enhances Testosterone Production in Mice and Their Testis-Derived Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Kota","family":"Shiozawa","sequence":"first","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misato","family":"Maeda","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8421-4919","authenticated-orcid":false,"given":"Hsin-Jung","family":"Ho","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Katsurai","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Zakir Hossain","family":"Howlader","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimiko","family":"Horiuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Sugita","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Ohsaki","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"},{"name":"International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afifah Zahra","family":"Agista","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Goto","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5325-988X","authenticated-orcid":false,"given":"Michio","family":"Komai","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4828-5274","authenticated-orcid":false,"given":"Hitoshi","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"},{"name":"International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"ref_1","first-page":"751","article-title":"Reference ranges of total serum and free testosterone in Japanese male adults","volume":"95","author":"Iwamoto","year":"2004","journal-title":"Nihon Hinyokika Gakkai Zasshi"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1056\/NEJMoa0911101","article-title":"Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men","volume":"363","author":"Wu","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1111\/andr.12770","article-title":"European Academy of Andrology (EAA) Guidelines on Investigation, Treatment and Monitoring of Functional Hypogonadism in Males: Endorsing Organization: European Society of Endocrinology","volume":"8","author":"Corona","year":"2020","journal-title":"Andrology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.yfrne.2013.09.001","article-title":"Sex differences in anxiety and depression: Role of testosterone","volume":"35","author":"McHenry","year":"2014","journal-title":"Front. Neuroendocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Payne, A.H., and Hardy, M.P. (2007). The Leydig Cell in Health and Disease, Humana Press.","DOI":"10.1007\/978-1-59745-453-7"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/1476-511X-10-158","article-title":"Menaquinone-4 Enhances Testosterone Production in Rats and Testis-Derived Tumor Cells","volume":"10","author":"Ito","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1080\/09168451.2015.1123612","article-title":"Geranylgeraniol Enhances Testosterone Production via the cAMP\/protein Kinase A Pathway in Testis-Derived I-10 Tumor Cells","volume":"80","author":"Ho","year":"2016","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1039\/c1fo10058k","article-title":"Dietary Vitamin K Alleviates the Reduction in Testosterone Production Induced by Lipopolysaccharide Administration in Rat Testis","volume":"2","author":"Takumi","year":"2011","journal-title":"Food Funct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1016\/j.bbagen.2006.05.008","article-title":"Vitamin K Deficiency Reduces Testosterone Production in the Testis through down-Regulation of the Cyp11a a Cholesterol Side Chain Cleavage Enzyme in Rats","volume":"1760","author":"Shirakawa","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jff.2016.08.008","article-title":"Effect of Kaempferia parviflora Extract and Its Polymethoxyflavonoid Components on Testosterone Production in Mouse Testis-Derived Tumour Cells","volume":"26","author":"Horigome","year":"2016","journal-title":"J. Funct. Foods"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Martin, L.J., and Touaibia, M. (2020). Improvement of Testicular Steroidogenesis Using Flavonoids and Isoflavonoids for Prevention of Late-Onset Male Hypogonadism. Antioxidants, 9.","DOI":"10.3390\/antiox9030237"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nakayama, Y., Ho, H.-J., Yamagishi, M., Ikemoto, H., Komai, M., and Shirakawa, H. (2020). Cysteine Sulfoxides Enhance Steroid Hormone Production via Activation of the Protein Kinase A Pathway in Testis-Derived I-10 Tumor Cells. Molecules, 25.","DOI":"10.3390\/molecules25204694"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rana, M.M., Shiozawa, K., Mukai, K., Takayanagi, K., Eguchi, K., Sultana, H., Ohsaki, Y., Komai, M., and Shirakawa, H. (2021). S-Allyl Cysteine Enhances Testosterone Production in Mice and Mouse Testis-Derived I-10 Cells. Molecules, 26.","DOI":"10.3390\/molecules26061697"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/biof.8","article-title":"Biotin","volume":"35","author":"Zempleni","year":"2009","journal-title":"Biofactors"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.nut.2008.06.031","article-title":"Effects of Biotin Deficiency on Embryonic Development in Mice","volume":"25","author":"Watanabe","year":"2009","journal-title":"Nutrition"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.steroids.2009.06.004","article-title":"Biotin deficiency and biotin excess: Effects on the female reproductive system","volume":"74","author":"Larrieta","year":"2009","journal-title":"Steroids"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1080\/09168451.2014.968090","article-title":"Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes","volume":"79","author":"Tsuji","year":"2015","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3177\/jnsv.43.271","article-title":"Biotin administration improves the impaired glucose tolerance of streptozotocin-induced diabetic Wistar rats","volume":"43","author":"Zhang","year":"1997","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.bbrc.2003.12.164","article-title":"Biotin Enhances ATP Synthesis in Pancreatic Islets of the Rat, Resulting in Reinforcement of Glucose-Induced Insulin Secretion","volume":"314","author":"Sone","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1271\/bbb.70781","article-title":"Effect of Biotin Treatment on Hepatic Gene Expression in Streptozotocin-Induced Diabetic Rats","volume":"72","author":"Sugita","year":"2008","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1039\/c2fo10175k","article-title":"Administration of biotin prevents the development of insulin resistance in the skeletal muscles of Otsuka long-Evans Tokushima fatty rats","volume":"3","author":"Sasaki","year":"2012","journal-title":"Food Funct."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1017\/S0007114507841122","article-title":"Antihypertensive Effect of Biotin in Stroke-Prone Spontaneously Hypertensive Rats","volume":"99","author":"Kamiyama","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref_23","first-page":"7276463","article-title":"Dietary Biotin Supplementation Modifies Hepatic Morphology without Changes in Liver Toxicity Markers","volume":"2016","year":"2016","journal-title":"Biomed Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1089\/jmf.2019.0137","article-title":"Dietary Biotin Supplementation Impairs Testis Morphology and Sperm Quality","volume":"23","year":"2020","journal-title":"J. Med. Food"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115774","DOI":"10.1016\/j.taap.2021.115774","article-title":"Dietary Biotin Supplementation Increases Proliferation Pathways in Mice Testes without Affecting Serum Follicle-Stimulating Hormone Levels and Stem Cell Factor Expression","volume":"433","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/cga.12070","article-title":"Dietary Intake of High-Dose Biotin Inhibits Spermatogenesis in Young Rats","volume":"55","author":"Sawamura","year":"2015","journal-title":"Congenit. Anom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0922-3371(90)90120-L","article-title":"A Mouse Embryonic Stem Cell Line Showing Pluripotency of Differentiation in Early Embryos and Ubiquitous \u03b2-Galactosidase Expression","volume":"29","author":"Suemori","year":"1990","journal-title":"Cell Differ. Dev."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sultana, H., Kato, A., Ohashi, A., Takashima, R., Katsurai, T., Sato, S., Monma, M., Ohsaki, Y., Goto, T., and Komai, M. (2021). Effect of Vitamin K-Mediated PXR Activation on Drug-Metabolizing Gene Expression in Human Intestinal Carcinoma LS180 Cell Line. Nutrients, 13.","DOI":"10.3390\/nu13051709"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.bbrc.2016.04.152","article-title":"Biotin Augments Acetyl CoA Carboxylase 2 Gene Expression in the Hypothalamus, Leading to the Suppression of Food Intake in Mice","volume":"476","author":"Sone","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/0143-4004(77)90006-6","article-title":"Characterization of a sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin and lipoate in human placental choriocarcinoma cells","volume":"18","author":"Prasad","year":"1997","journal-title":"Placenta"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Banihani, S.A. (2018). Ginger and Testosterone. Biomolecules, 8.","DOI":"10.3390\/biom8040119"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Banihani, S.A. (2019). Testosterone in Males as Enhanced by Onion (Allium cepa L.). Biomolecules, 9.","DOI":"10.3390\/biom9020075"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/S0962-8924(02)02294-8","article-title":"Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation","volume":"12","author":"Stork","year":"2002","journal-title":"Trends Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35454","DOI":"10.18632\/oncotarget.7721","article-title":"Control of CREB expression in tumors: From molecular mechanisms and signal transduction pathways to therapeutic target","volume":"7","author":"Steven","year":"2016","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cui, Q.L., Lin, Y.H., Xu, Y.K.T., Fernandes, M.G.F., Rao, V.T.S., Kennedy, T.E., and Antel, J. (2020). Effects of biotin on survival, ensheathment, and ATP production by oligodendrocyte lineage cells in vitro. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0233859"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.jnutbio.2009.03.009","article-title":"Biotin increases glucokinase expression via soluble guanylate cyclase\/protein kinase G, adenosine triphosphate production and autocrine action of insulin in pancreatic rat islets","volume":"21","author":"Tovar","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1089\/jmf.2014.0170","article-title":"Effects of Biotin Supplementation in the Diet on Adipose Tissue cGMP Concentrations, AMPK Activation, Lipolysis, and Serum-Free Fatty Acid Levels","volume":"18","year":"2015","journal-title":"J. Med. Food"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.ymgme.2005.04.001","article-title":"Biotin Availability Regulates Expression of the Sodium-Dependent Multivitamin Transporter and the Rate of Biotin Uptake in HepG2 Cells","volume":"85","author":"Michalak","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.taap.2013.04.028","article-title":"Bisphenol A Down-regulates Rate-Limiting Cyp11a1 to Acutely Inhibit Steroidogenesis in Cultured Mouse Antral Follicles","volume":"271","author":"Peretz","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10373","DOI":"10.1096\/fj.202000361R","article-title":"Ablation of the Canonical Testosterone Production Pathway via Knockout of the Steroidogenic Enzyme HSD17B3, Reveals a Novel Mechanism of Testicular Testosterone Production","volume":"34","author":"Rebourcet","year":"2020","journal-title":"FASEB J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.theriogenology.2019.05.023","article-title":"Protective Effects of L-Arginine against Testosterone Synthesis Decreased by T-2 Toxin in Mouse Leydig Cells","volume":"134","author":"Yang","year":"2019","journal-title":"Theriogenology"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/22\/4761\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:14:15Z","timestamp":1760145255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/22\/4761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":41,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["nu14224761"],"URL":"https:\/\/doi.org\/10.3390\/nu14224761","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]}}}