{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T13:44:43Z","timestamp":1782308683258,"version":"3.54.5"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2017,3,16]],"date-time":"2017-03-16T00:00:00Z","timestamp":1489622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"TENOVUS SCOTLAND"},{"name":"Chief Scientist Office\/NHS research Scotland"},{"name":"University of Abertay"},{"name":"Infertility Research Trust"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,5,1]]},"DOI":"10.1093\/humrep\/dex055","type":"journal-article","created":{"date-parts":[[2017,3,2]],"date-time":"2017-03-02T15:10:15Z","timestamp":1488467415000},"page":"974-984","source":"Crossref","is-referenced-by-count":21,"title":["Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem"],"prefix":"10.1093","volume":"32","author":[{"given":"Sarah J.","family":"Martins da Silva","sequence":"first","affiliation":[{"name":"Reproductive and Developmental Biology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK"},{"name":"Assisted Conception Unit, Ninewells Hospital, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean G.","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Science Engineering and Technology, University of Abertay, Dundee DD1 1HG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Sutton","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise V.","family":"King","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halil","family":"Ruso","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Gray","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Wyatt","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.R.","family":"Barratt","sequence":"additional","affiliation":[{"name":"Reproductive and Developmental Biology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK"},{"name":"Assisted Conception Unit, Ninewells Hospital, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony G.","family":"Hope","sequence":"additional","affiliation":[{"name":"Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,3,16]]},"reference":[{"key":"key\n\t\t\t\t20180328141910_dex055C1","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1093\/humrep\/des467","article-title":"The clinical significance of calcium-signalling pathways mediating human sperm hyperactivation","volume":"28","author":"Alasmari","year":"2013","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C2","doi-asserted-by":"crossref","first-page":"6248","DOI":"10.1074\/jbc.M112.439356","article-title":"Ca2+ signals generated by CatSper and Ca2+ stores regulate different behaviors in human sperm","volume":"288","author":"Alasmari","year":"2013","journal-title":"J Biol Chem"},{"key":"key\n\t\t\t\t20180328141910_dex055C3","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.fertnstert.2016.08.036","article-title":"Male contraception","volume":"106","author":"Amory","year":"2016","journal-title":"Fertil Steril"},{"key":"key\n\t\t\t\t20180328141910_dex055C4","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1021\/jm3011433","article-title":"Ion channels as therapeutic targets: a drug discovery perspective","volume":"56","author":"Bagal","year":"2013","journal-title":"J Med Chem"},{"key":"key\n\t\t\t\t20180328141910_dex055C5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.mce.2009.02.006","article-title":"Nongenomic activation of spermatozoa by steroid hormones: facts and fictions","volume":"308","author":"Baldi","year":"2009","journal-title":"Mol Cell Endocrinol"},{"key":"key\n\t\t\t\t20180328141910_dex055C6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/aja.2010.63","article-title":"Diagnostic tools in male infertility-the question of sperm dysfunction","volume":"13","author":"Barratt","year":"2011","journal-title":"Asian J Androl"},{"key":"key\n\t\t\t\t20180328141910_dex055C7","first-page":"227","article-title":"\u2018How to count sperm properly\u2019: checklist for acceptability of studies based on human semen analysis","volume":"31","author":"Bjorndahl","year":"2016","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C8","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1038\/emboj.2012.30","article-title":"The CatSper channel: a polymodal chemosensor in human sperm","volume":"31","author":"Brenker","year":"2012","journal-title":"EMBO J"},{"key":"key\n\t\t\t\t20180328141910_dex055C9","first-page":"14","article-title":"High-throughput screening for drug discovery","volume":"384","author":"Broach","year":"1996","journal-title":"Nature"},{"key":"key\n\t\t\t\t20180328141910_dex055C10","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1093\/humrep\/dew056","article-title":"Depolarization of sperm membrane potential is a common feature of men with subfertility and is associated with low fertilization rate at IVF","volume":"31","author":"Brown","year":"2016","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C11","doi-asserted-by":"crossref","first-page":"e6844","DOI":"10.1371\/journal.pone.0006844","article-title":"Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation","volume":"4","author":"Carlson","year":"2009","journal-title":"PLoS One"},{"key":"key\n\t\t\t\t20180328141910_dex055C12","doi-asserted-by":"crossref","first-page":"14864","DOI":"10.1073\/pnas.2536658100","article-title":"CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm","volume":"100","author":"Carlson","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"key\n\t\t\t\t20180328141910_dex055C13","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1093\/humupd\/dmp048","article-title":"World Health Organization reference values for human semen characteristics","volume":"16","author":"Cooper","year":"2010","journal-title":"Hum Reprod Update"},{"key":"key\n\t\t\t\t20180328141910_dex055C14","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/01485010390219656","article-title":"Asthenozoospermia: analysis of a large population","volume":"49","author":"Curi","year":"2003","journal-title":"Arch Androl"},{"key":"key\n\t\t\t\t20180328141910_dex055C15","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1152\/physrev.00028.2010","article-title":"Calcium channels in the development, maturation, and function of spermatozoa","volume":"91","author":"Darszon","year":"2011","journal-title":"Physiol Rev"},{"key":"key\n\t\t\t\t20180328141910_dex055C16","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1093\/humrep\/dew123","article-title":"Prevalence of infertility and help seeking among 15000 women and men","volume":"31","author":"Datta","year":"2016","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C17","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","article-title":"Innovation in the pharmaceutical industry: new estimates of R&D costs","volume":"47","author":"DiMasi","year":"2016","journal-title":"J Health Econ"},{"key":"key\n\t\t\t\t20180328141910_dex055C18","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1053\/beem.2000.0083","article-title":"Molecular and cellular mechanisms in spermatogenesis","volume":"14","author":"Grootegoed","year":"2000","journal-title":"Baillieres Best Pract Res Clin Endocrinol Metab"},{"key":"key\n\t\t\t\t20180328141910_dex055C19","author":"HFEA","year":"2014"},{"key":"key\n\t\t\t\t20180328141910_dex055C20","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1038\/ejhg.2010.108","article-title":"Genetic male infertility and mutation of CATSPER ion channels","volume":"18","author":"Hildebrand","year":"2010","journal-title":"Eur J Hum Genet"},{"key":"key\n\t\t\t\t20180328141910_dex055C21","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1006\/dbio.2002.0797","article-title":"Hyperactivated motility of bull sperm is triggered at the axoneme by Ca2+ and not cAMP","volume":"250","author":"Ho","year":"2002","journal-title":"Dev Biol"},{"key":"key\n\t\t\t\t20180328141910_dex055C22","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1095\/biolreprod65.5.1606","article-title":"An inositol 1,4,5-trisphosphate receptor-gated intracellular Ca(2+) store is involved in regulating sperm hyperactivated motility","volume":"65","author":"Ho","year":"2001","journal-title":"Biol Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C23","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1095\/biolreprod.102.011320","article-title":"Characterization of the intracellular calcium store at the base of the sperm flagellum that regulates hyperactivated motility","volume":"68","author":"Ho","year":"2003","journal-title":"Biol Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C24","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1071\/RD08183","article-title":"CatSper-null mutant spermatozoa are unable to ascend beyond the oviductal reservoir","volume":"21","author":"Ho","year":"2009","journal-title":"Reprod Fertil Dev"},{"key":"key\n\t\t\t\t20180328141910_dex055C25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/humrep\/17.1.143","article-title":"Critical evaluation of methylcellulose as an alternative medium in sperm migration tests","volume":"17","author":"Ivic","year":"2002","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C26","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tcb.2016.10.002","article-title":"Signaling in sperm: more different than similar","volume":"2","author":"Kaupp","year":"2017","journal-title":"Trends Cell Biol"},{"key":"key\n\t\t\t\t20180328141910_dex055C27","first-page":"209","article-title":"A simple sperm penetration test","volume":"10","author":"Kremer","year":"1965","journal-title":"Int J Fertil"},{"key":"key\n\t\t\t\t20180328141910_dex055C28","first-page":"233","article-title":"Assisted reproductive technology in Europe, 2011: results generated from European registers by ESHRE","volume":"31","author":"Kupka","year":"2016","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C29","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1093\/humrep\/deu175","article-title":"Assisted reproductive technology in Europe, 2010: results generated from European registers by ESHRE","volume":"29","author":"Kupka","year":"2014","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C30","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nature09767","article-title":"Progesterone activates the principal Ca2+ channel of human sperm","volume":"471","author":"Lishko","year":"2011","journal-title":"Nature"},{"key":"key\n\t\t\t\t20180328141910_dex055C31","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/molehr\/gau003","article-title":"Patch clamp studies of human sperm under physiological ionic conditions reveal three functionally and pharmacologically distinct cation channels","volume":"20","author":"Mansell","year":"2014","journal-title":"Mol Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C32","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ydbio.2006.11.007","article-title":"Contributions of extracellular and intracellular Ca2+ to regulation of sperm motility: Release of intracellular stores can hyperactivate CatSper1 and CatSper2 null sperm","volume":"303","author":"Marquez","year":"2007","journal-title":"Dev Biol"},{"key":"key\n\t\t\t\t20180328141910_dex055C33","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2174\/156802606775193347","article-title":"Recent developments in focused library design: targeting gene-families","volume":"6","author":"Miller","year":"2006","journal-title":"Curr Top Med Chem"},{"key":"key\n\t\t\t\t20180328141910_dex055C34","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1021\/ci200260t","article-title":"Mining the ChEMBL database: an efficient chemoinformatics workflow for assembling an ion channel-focused screening library","volume":"51","author":"Mok","year":"2011","journal-title":"J Chem Inf Model"},{"key":"key\n\t\t\t\t20180328141910_dex055C35","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/ncb0307-235","article-title":"[Ca2+]i signalling in sperm--making the most of what you've got","volume":"9","author":"Publicover","year":"2007","journal-title":"Nat Cell Biol"},{"key":"key\n\t\t\t\t20180328141910_dex055C36","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1093\/molehr\/gar048","article-title":"Sperm motility: things are moving in the lab","volume":"17","author":"Publicover","year":"2011","journal-title":"Mol Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C37","doi-asserted-by":"crossref","first-page":"14869","DOI":"10.1073\/pnas.2136654100","article-title":"Hyperactivated sperm motility driven by CatSper2 is required for fertilization","volume":"100","author":"Quill","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"key\n\t\t\t\t20180328141910_dex055C38","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/35098027","article-title":"A sperm ion channel required for sperm motility and male fertility","volume":"413","author":"Ren","year":"2001","journal-title":"Nature"},{"key":"key\n\t\t\t\t20180328141910_dex055C39","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1097\/GCO.0000000000000261","article-title":"The impact of stress on fertility treatment","volume":"3","author":"Rooney","year":"2016","journal-title":"Curr Opin Obstet Gynecol"},{"key":"key\n\t\t\t\t20180328141910_dex055C40","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/cm.970270303","article-title":"Role of cAMP in the reactivation of demembranated ram spermatozoa","volume":"27","author":"San Agustin","year":"1994","journal-title":"Cell Motil Cytoskeleton"},{"key":"key\n\t\t\t\t20180328141910_dex055C41","doi-asserted-by":"crossref","first-page":"758","DOI":"10.15252\/embr.201438869","article-title":"Direct action of endocrine disrupting chemicals on human sperm","volume":"15","author":"Schiffer","year":"2014","journal-title":"EMBO Rep"},{"key":"key\n\t\t\t\t20180328141910_dex055C42","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1093\/humrep\/des070","article-title":"Estimation of the frequency of involuntary infertility on a nation-wide basis","volume":"27","author":"Slama","year":"2012","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C43","doi-asserted-by":"crossref","first-page":"6823","DOI":"10.1073\/pnas.1216588110","article-title":"Disruption of the principal, progesterone-activated sperm Ca2+ channel in a CatSper2-deficient infertile patient","volume":"110","author":"Smith","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"key\n\t\t\t\t20180328141910_dex055C44","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/nature09769","article-title":"The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm","volume":"471","author":"Strunker","year":"2011","journal-title":"Nature"},{"key":"key\n\t\t\t\t20180328141910_dex055C45","first-page":"1","article-title":"Assisted reproductive technology surveillance--United States, 2011","volume":"63","author":"Sunderam","year":"2014","journal-title":"MMWR Surveill Summ"},{"key":"key\n\t\t\t\t20180328141910_dex055C46","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1093\/humrep\/deu196","article-title":"Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity","volume":"29","author":"Tardif","year":"2014","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C47","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1095\/biolreprod26.4.745","article-title":"Regulation of protein phosphorylation and motility of sperm by cyclic adenosine monophosphate and calcium","volume":"26","author":"Tash","year":"1982","journal-title":"Biol Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C48","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1095\/biolreprod28.1.75","article-title":"Cyclic adenosine 3\u2032,5\u2032 monophosphate, calcium and protein phosphorylation in flagellar motility","volume":"28","author":"Tash","year":"1983","journal-title":"Biol Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C49","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1093\/humrep\/det372","article-title":"p,p\u2032-DDE activates CatSper and compromises human sperm function at environmentally relevant concentrations","volume":"28","author":"Tavares","year":"2013","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C50","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.fertnstert.2010.02.024","article-title":"Role of semen analysis in subfertile couples","volume":"95","author":"van der Steeg","year":"2011","journal-title":"Fertil Steril"},{"key":"key\n\t\t\t\t20180328141910_dex055C51","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.rbmo.2013.10.021","article-title":"IVF with planned single-embryo transfer versus IUI with ovarian stimulation in couples with unexplained subfertility: an economic analysis","volume":"28","author":"van Rumste","year":"2014","journal-title":"Reprod Biomed Online"},{"key":"key\n\t\t\t\t20180328141910_dex055C52","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4103\/0970-1591.78424","article-title":"Semen analysis and sperm function tests: How much to test","volume":"27","author":"Vasan","year":"2011","journal-title":"Indian J Urol"},{"key":"key\n\t\t\t\t20180328141910_dex055C53","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1006\/dbio.1997.8768","article-title":"Regulation, localization, and anchoring of protein kinase A subunits during mouse sperm capacitation","volume":"192","author":"Visconti","year":"1997","journal-title":"Dev Biol"},{"key":"key\n\t\t\t\t20180328141910_dex055C54","first-page":"2737","article-title":"Specific loss of CatSper function is sufficient to compromise fertilizing capacity of human spermatozoa","volume":"30","author":"Williams","year":"2015","journal-title":"Hum Reprod"},{"key":"key\n\t\t\t\t20180328141910_dex055C55","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1085\/jgp.201311011","article-title":"Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa","volume":"142","author":"Zeng","year":"2013","journal-title":"J Gen Physiol"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/humrep\/article-pdf\/32\/5\/974\/24265440\/dex055.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,3,28]],"date-time":"2018-03-28T16:06:28Z","timestamp":1522253188000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/32\/5\/974\/3072819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,16]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,3,16]]},"published-print":{"date-parts":[[2017,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/dex055","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,5]]},"published":{"date-parts":[[2017,3,16]]}}}