{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:01:44Z","timestamp":1791414104290,"version":"4.3.3"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T00:00:00Z","timestamp":1606694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There has been a recent upsurge in the interest about contraceptive development, evidenced by the Contraceptive Special Issue of Biology of Reproduction [1], with research funding from the Male Contraceptive Initiative and the Bill and Melinda Gates Foundation. Support from the Contraceptive Research Branch of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development continues with a marked change in focus in the funding announcements. This has motivated me to reflect on research, mostly from my laboratory starting in the 1960s to the present, on the development of a male contraceptive based on the sperm-specific glycolytic enzyme, lactate dehydrogenase C (LDHC4). This review considers the rationale behind this research, the development paths pursued, obstacles encountered, and the renewed interest in going forward toward development of a male contraceptive mediated by the inhibition of the sperm-specific form of LDHC. I will address how some papers published many years ago are relevant to the present goals of non-hormonal contraception and will mention about innovative technology now available that can advance this project. This review presumably will serve as an instructive guide for a research program with a focused program related to contraception. As an aside, many of the citations in this review are to most of the 26 publications in Biology of Reproduction co-authored by this investigator and collaborators from 1974 through 2020 not long after the first issue of BOR which was published in April 1969.<\/jats:p>","DOI":"10.1093\/biolre\/ioaa217","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T10:06:53Z","timestamp":1606730813000},"page":"521-526","source":"Crossref","is-referenced-by-count":25,"title":["The sperm-specific form of lactate dehydrogenase is required for fertility and is an attractive target for male contraception (a review)"],"prefix":"10.1093","volume":"104","author":[{"given":"Erwin","family":"Goldberg","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,30]]},"reference":[{"key":"2021031607171809200_ref1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/biolre\/ioaa120","volume":"103","author":"Matzuk","year":"2020","journal-title":"Biol Reprod"},{"key":"2021031607171809200_ref2","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1111\/j.1749-6632.1961.tb35565.x","article-title":"Physicochemical nature of isozvmes","volume":"94","author":"Markert","year":"1961","journal-title":"Ann N Y Acad Sci"},{"key":"2021031607171809200_ref3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/9780470110201.ch7","article-title":"Determination of serum acid phosphatases","volume":"4","author":"Fishman","year":"1957","journal-title":"Methods Biochem Anal"},{"key":"2021031607171809200_ref4","first-page":"150","article-title":"A serum alkaline phosphatase isoenzyme of human neoplastic cell origin","volume":"1","author":"Fishman","year":"1968","journal-title":"Cancer Res"},{"key":"2021031607171809200_ref5","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1126\/science.139.3555.601","article-title":"Lactate dehydrogenases in human testes","volume":"139","author":"Blanco","year":"1963","journal-title":"Science"},{"key":"2021031607171809200_ref6","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1126\/science.139.3555.602","article-title":"Lactic and malic dehydrogenases in human spermatozoa","volume":"139","author":"Goldberg","year":"1963","journal-title":"Science"},{"key":"2021031607171809200_ref7","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1126\/science.130.3376.624","article-title":"Effect of light on motility, life-span and respiration of bovine spermatozoa","volume":"130","author":"Norman","year":"1959","journal-title":"Science"},{"key":"2021031607171809200_ref8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/jcp.1030580208","article-title":"The metabolism of ejaculated spermatozoa from the fowl","volume":"58","author":"Goldberg","year":"1961","journal-title":"J Cell Comp Physiol"},{"key":"2021031607171809200_ref9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/0003-9861(65)90298-5","article-title":"Lactate dehydrogenases in spermatozoa: Subunit interactions in vitro","volume":"109","author":"Goldberg","year":"1965","journal-title":"Arch Biochem Biophys"},{"key":"2021031607171809200_ref10","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/jez.1401640302","article-title":"The ontogeny of sperm specific lactate dehydrogenase in mice","volume":"164","author":"Goldberg","year":"1967","journal-title":"J Exp Zool"},{"key":"2021031607171809200_ref11","first-page":"219","article-title":"Locus determining the human sperm-specific lactate dehydrogenase, LDHC, is syntenic with LDHA","volume":"8","author":"Edwards","year":"1987","journal-title":"Development"},{"key":"2021031607171809200_ref12","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1111\/j.1749-6632.1964.tb14226.x","article-title":"Lactate dehydrogenases and malate dehydrogenases in sperm: studied by polyacrylamide gel electrophoresis","volume":"121","author":"Goldberg","year":"1964","journal-title":"Ann N Y Acad Sci"},{"key":"2021031607171809200_ref13","first-page":"13","volume-title":"Immunological Approaches to Fertility Control","author":"Diczfalusy","year":"1974"},{"key":"2021031607171809200_ref14","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1126\/science.176.4035.686","article-title":"Pregnancy suppression by an antiserum to the sperm specific lactate dehydrogenase","volume":"176","author":"Goldberg","year":"1972","journal-title":"Science"},{"key":"2021031607171809200_ref15","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1126\/science.181.4098.458","article-title":"Infertility in female rabbits immunized with lactate dehydrogenase X","volume":"181","author":"Goldberg","year":"1973","journal-title":"Science"},{"key":"2021031607171809200_ref16","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/jez.1401890215","article-title":"Binding of antibody to LDH-X by the mouse blastocyst","volume":"189","author":"Bene","year":"1974","journal-title":"J Exp Zool"},{"key":"2021031607171809200_ref17","doi-asserted-by":"crossref","first-page":"502","DOI":"10.2164\/jandrol.05185","article-title":"Testis-specific lactate dehydrogenase (LDH-C4; Ldh3) in murine oocytes and preimplantation embryos","volume":"27","author":"Coonrod","year":"2006","journal-title":"J Androl"},{"key":"2021031607171809200_ref18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0165-0378(01)00102-4","article-title":"Oolemmal proteomics","volume":"53","author":"Coonrod","year":"2002","journal-title":"J Reprod Immunol"},{"key":"2021031607171809200_ref19","doi-asserted-by":"crossref","first-page":"10513","DOI":"10.1016\/S0021-9258(18)81651-9","article-title":"Immunogenicity of synthetic peptides corresponding to flexible and antibody-accessible segments of mouse lactatedehydrogenase (LDH)-C4","volume":"264","author":"Hogrefe","year":"1989","journal-title":"J Biol Chem"},{"key":"2021031607171809200_ref20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1021\/bi00453a002","article-title":"Synthesis and biophysical characterization of engineered topographic immunogenic determinants with \u03b1\u03b1 topology","volume":"29","author":"Kaumaya","year":"1990","journal-title":"Biochemistry"},{"key":"2021031607171809200_ref21","first-page":"394","volume-title":"Proc. Intern. Symp. Control. Rel. Bioact. Mater., Controlled Release Society","author":"O'Hern","year":"1993"},{"key":"2021031607171809200_ref22","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1016\/S0264-410X(97)00105-9","article-title":"Colinear synthesis of an antigen-specific B-cell epitope with a \u201cpromiscuous\u201d tetanus toxin T-cell epitope: a synthetic peptide immunocontraceptive","volume":"16","author":"O'Hern","year":"1997","journal-title":"Vaccine"},{"key":"2021031607171809200_ref23","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/978-1-4613-2255-9_21","volume-title":"The Molecular and Cellular Biology of Fertilization: Advances in Experimental Medicine and Biology","author":"Goldberg","year":"1986"},{"key":"2021031607171809200_ref24","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1095\/biolreprod52.2.331","article-title":"Reversible contraception in female baboons immunized with a synthetic epitope of sperm-specific lactate dehydrogenase","volume":"52","author":"O'Hern","year":"1995","journal-title":"Biol Reprod"},{"key":"2021031607171809200_ref25","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3109\/01485018508986907","article-title":"Semen LDH-X deficiency and male infertility","volume":"15","author":"Gavella","year":"1985","journal-title":"Arch Androl"},{"key":"2021031607171809200_ref26","first-page":"2471","article-title":"Aberrant expression of sperm-specific glycolytic enzymes are associated with poor sperm quality","volume":"19","author":"Liu","year":"2019","journal-title":"Mol Med Rep"},{"key":"2021031607171809200_ref27","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1016\/S0021-9258(19)45488-4","article-title":"Amino acid composition and properties of crystalline lactate dehydrogenase X from mouse testes","volume":"247","author":"Goldberg","year":"1972","journal-title":"J Biol Chem"},{"key":"2021031607171809200_ref28","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/0012-1606(77)90222-6","article-title":"Immunohistochemical localization of LDHX during spermatogenesis in mouse testes","volume":"57","author":"Hintz","year":"1977","journal-title":"Dev Biol"},{"key":"2021031607171809200_ref29","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.compbiolchem.2009.07.006","article-title":"Computational analyses of mammalian lactate dehydrogenases: human, mouse, opossum and platypus LDHs","volume":"33","author":"Holmes","year":"2009","journal-title":"Comput Biol Chem"},{"key":"2021031607171809200_ref30","doi-asserted-by":"crossref","first-page":"13155","DOI":"10.1016\/S0021-9258(18)45181-2","article-title":"Characterization of antigenic sites on the refined 3-A resolution structure of mouse testicular lactate dehydrogenase-C4","volume":"262","author":"Hogrefe","year":"1987","journal-title":"J Biol Chem"},{"key":"2021031607171809200_ref31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1095\/biolreprod.108.068353","article-title":"Expression of the gene for lactate dehydrogense C (Ldhc) is required for male fertility","volume":"79","author":"Odet","year":"2008","journal-title":"Biol Reprod"},{"key":"2021031607171809200_ref32","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1095\/biolreprod.111.091546","article-title":"Lactate dehydrogenase C and energy metabolism in mouse sperm","volume":"85","author":"Odet","year":"2011","journal-title":"Biol Reprod"},{"key":"2021031607171809200_ref33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2164\/jandrol.109.008367","article-title":"LDHC the ultimate testis specific gene","volume":"31","author":"Goldberg","year":"2010","journal-title":"J Androl"},{"key":"2021031607171809200_ref34","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0167-4838(97)00090-3","article-title":"Selective inhibition of the sperm-specific lactate dehydrogenase isozyme-C4 by N-isopropyl oxamate","volume":"1343","author":"Wong","year":"1997","journal-title":"Biochim Biophys Acta"},{"key":"2021031607171809200_ref35","doi-asserted-by":"crossref","first-page":"579","DOI":"10.3109\/14756366.2011.566221","article-title":"Oxamic acid analogues as LDH-C4-specific competitive inhibitors","volume":"26","author":"Rodr\u00edguez-P\u00e1ez","year":"2011","journal-title":"J Enzyme Inhib Med Chem"},{"key":"2021031607171809200_ref36","doi-asserted-by":"crossref","DOI":"10.1186\/s40170-016-0145-9","article-title":"Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism","volume":"4","author":"Otto","year":"2016","journal-title":"Cancer Metab"},{"key":"2021031607171809200_ref37","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s11010-012-1428-2","article-title":"LDH-4: a target with therapeutic potential for cancer and contraception","volume":"371","author":"Gupta","year":"2012","journal-title":"Mol Cell Biochem"},{"key":"2021031607171809200_ref38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0006-2952(01)00636-0","article-title":"Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4","volume":"62","author":"Yu","year":"2001","journal-title":"Biochem Pharmacol"},{"key":"2021031607171809200_ref39","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1159\/000076824","article-title":"Inhibition of lactate dehydrogenase C4 (LDH-C4) blocks capacitation of mouse sperm in vitro","volume":"103","author":"Duan","year":"2003","journal-title":"Cytogenet Genome Res"},{"key":"2021031607171809200_ref40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/biolre\/ioaa076","article-title":"Preclinical contraceptive development for men and women","volume":"103","author":"Johnston","year":"2020","journal-title":"Biol Reprod"},{"key":"2021031607171809200_ref41","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1146\/annurev-biochem-062917-012550","article-title":"DNA-encoded chemical libraries: a selection system based on endowing organic compounds with amplifiable information","volume":"87","author":"Neri","year":"2018","journal-title":"Annu Rev Biochem"},{"key":"2021031607171809200_ref42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrd.2016.211","article-title":"Induced protein degradation: an emerging drug discovery paradigm","volume":"16","author":"Lai","year":"2017","journal-title":"Nat Rev Drug Discov"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioaa217\/34593268\/ioaa217.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/biolreprod\/article-pdf\/104\/3\/521\/36605204\/ioaa217.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/biolreprod\/article-pdf\/104\/3\/521\/36605204\/ioaa217.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T06:57:02Z","timestamp":1697266622000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/104\/3\/521\/6008540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,30]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,11,30]]},"published-print":{"date-parts":[[2021,3,11]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioaa217","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,3]]},"published":{"date-parts":[[2020,11,30]]}}}