A new selection of articles published recently in the field of andrology andreproductivebiology.Inthisedition,thereissomethingforeveryone,includingnew studies of male infertility, falling sperm counts, COVID-19 and sperm,reproductive ageing issues, management of LUTS and Klinefelter syndrome,semen microbiome, androgen signalling in prostate cancer, and more. EAAmembershavecontributedtoanumberofthesepapers. Ifyoufeelthatyourworkshouldbehighlightedinthesealerts,sendanotetotheEAASecretary.

An important international project addressingcouple infertility has been formally launched byresearchersfromEAACentresinCopenhagenandMalmö. The cohort: ReproUnion Biobank andInfertilityCohort(RUBIC)willinclude5000couplesundergoing fertilitymanagement. The project willinvestigate risk factors for infertility and adversepregnancyoutcomes;developnewdiagnosticandprognosticbiomarkersforfecundityandtreatmentsuccess, and study health characteristics ofinfertilepeopleduringlong-termfollow-up.

PriskornL,TøttenborgSS,AlmstrupK,AnderssonAM,AxelssonJ,BräunerEV,ElenkovA,FreieslebenNC,GiwercmanYL,GrøndahlML,HansenAH,HansenLS,HenicE,KitlinskiML,LandersoeSK,LindhC,LøkkegaardEL,MalmJ,OlsenKW,PetersenKU,SchmidtL,StormlundS,SvendsenPF,VassardD,WangNF,ZedelerA,BhasinS,ChavarroJ,EisenbergML,HauserR,HuhtaniemiI,KrawetzSA,Marko-VargaG,SaloniaA,ToppariJ,JuulA,JørgensenN,NielsenHS,PinborgA,RylanderL,GiwercmanA.RUBIC-Abinationalclinicalfoundationtostudyriskfactors,lifecourse,andtreatmentofinfertilityandinfertility-relatedmorbidity.Andrology.2021Jun10.doi:10.1111/andr.13063.Epubaheadofprint.PMID:34114375.https://onlinelibrary.wiley.com/doi/10.1111/andr.13063

This study investigated possible thresholds forspermparameters thatcouldpredictearlier time-to-conception in couples undergoing fertilityevaluation. The authors compared the semenanalysisdataandthefollow-upconceptiondataina large cohort of men from subfertile couplesdivided into groups with natural conception orhelpedwithART.Intheoverallcohort,athresholdof50milliontotalprogressivemotilespermcountprovided the best predictive power to estimateearliertime-to-conception.

KeihaniS,VerrilliLE,ZhangC,PressonAP,HansonHA,PastuszakAW,JohnstoneEB,HotalingJM.Semenparameterthresholdsandtime-to-conceptioninsubfertilecouples:howhighishighenough?HumanReproduction.2021Jun7:deab133.doi:10.1093/humrep/deab133.Epubaheadofprint.PMID:34097024.

https://academic.oup.com/humrep/advance-article-abstract/doi/10.1093/humrep/deab133/6294420?redirectedFrom=fulltext

A study from Denmark showing that abuse of

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EAALiteratureAlertEditionJune2021

Clinicalandrologyandepidemiology

anabolicandrogenicsteroids (AAS) isnotagoodidea!SerumINSL3isreducedyearsfollowingAAScessation inmen, independentlyoftestosterone,suggesting persistently impaired Leydig cellcapacity.RasmussenJJ,AlbrethsenJ,FrandsenMN,JørgensenN,JuulA,KistorpC.SerumInsulin-likeFactor3LevelsAreReducedinFormerAndrogenUsers,SuggestingImpairedLeydigCellCapacity.J.Clin.Endocrinol.Metab.2021Jun16;106(7):e2664-e2672.doi:10.1210/clinem/dgab129.PMID:33693710.

https://academic.oup.com/jcem/article-abstract/106/7/e2664/6156950?redirectedFrom=fulltext

This study based on >6800 injections in 325patientsattempted todefine theoptimized inter-injection interval of injectable testosteroneundecanoate(TU)treatmentforhypogonadalandtransmen. The optimal injection interval had amedian of 12.0 weeks (interquartile range 10.4-12.7 weeks). The interval was significantlyinfluencedbyageandbodysize.ShankaraNarayanaN,LyLP,JayadevV,FennellC,SavkovicS,ConwayAJ,HandelsmanDJ.Optimalinjectionintervalfortestosteroneundecanoatetreatmentofhypogonadalandtransgendermen.EndocrineConnections2021Jun1:EC-21-0109.R2.doi:10.1530/EC-21-0109.PMID:34137730.

https://ec.bioscientifica.com/view/journals/ec/aop/ec-21-0109/ec-21-0109.xml

What is thebestmodeofhormonal treatmentofmen with Klinefelter syndrome? This Danishretrospective study evaluated testosteronereplacement therapy (TRT) by injection,transdermallyornone.Irrespectiveoftherouteofadministration,TRTaffectedandrogen-responsivevariablessimilarly inKSmen.Cliniciansshouldbeencouraged to seek the route of administrationresulting in the highest degree of adhesion totreatmentbasedonindividualpatientpreferences.ApiraaKabilan,AnneSkakkebæk,SimonChang,ClausHGravholt,EvaluationoftheEfficacyofTransdermalandInjectionTestosteroneTherapyinKlinefelterSyndrome:AReal-LifeStudy,JournaloftheEndocrineSociety(JAS),June2021,5(6),bvab062,doi.org/10.1210/jendso/bvab062.

Concentrations of estradiol, estrone andtestosterone(T)arehigherinelderlymenthaninwomen.Menwith higher BMI had lower T, lowerprecursors (exceptpregnenolone)andSHBGbuthigher estrone levels. This was shown in aprospectiveSwedishstudyofacohortofhealthy70-year-oldmenandwomen.Thepaperprovidedalso LC-MS/MS-based concentrations ofendogenousadrenalandsexsteroidsinthisagegroup.PenellJC,KushnirMM,LindL,BergquistJ,BergquistJ,LindPM,NaessenT.Concentrationsofnineendogenoussteroidhormonesin70-year-oldmenandwomen.EndocrineConnections2021May13;10(5):511-520.doi:10.1530/EC-21-0045.PMID:33878730.

https://ec.bioscientifica.com/view/journals/ec/10/5/EC-21-0045.xml

Somehelphowtomanagethemalelowerurinarytract symptoms (LUTS), especially in older men.Theauthorsreviewedandevaluatedthequalityofevidence (according to GRADE guidelines)regarding the values, preferences, andexpectationsofmentowardstheinvestigationandtreatment (conservative, pharmacological, andsurgical)ofLUTS.Menpreferredconservativeand

lessriskytreatmentoptionsthathavefewersexualsideeffectsandareprimarilyeffectiveatimprovingurgencyincontinenceandnocturia.

MaldeS,UmbachR,WheelerJR,LytvynL,CornuJN,GacciM,GratzkeC,HerrmannTRW,MamoulakisC,RiekenM,SpeakmanMJ,GravasS,DrakeMJ,GuyattGH,TikkinenKAO.ASystematicReviewofPatients'Values,Preferences,andExpectationsfortheDiagnosisandTreatmentofMaleLowerUrinaryTractSymptoms.EuropeanUrology2021;79(6):796-809.doi:10.1016/j.eururo.2020.12.019.PMID:33461781.

https://www.sciencedirect.com/science/article/abs/pii/S0302283821002499?via%3DihubEditors’Commentary:https://www.sciencedirect.com/science/article/abs/pii/S0302283821002499?via%3DihubCommentarybyNunzioetal:MaleLowerUrinaryTractSymptomsandBenignProstaticObstruction:WhatDoPatientsWant?-ScienceDirect

A study from the European Male Aging Study(EMAS) Consortium, with contribution of severalEAA Academicians, addressed a rarely studiedproblemofshorterthandesiredejaculationlatency(rapid ejaculation, RE) and its related distressamongmiddle-aged and oldermen (>2800, age40-79). The study was based on self-reportedsexualfunctionquestionnaireandfoundthatREisafrequentcondition(>30%)butcausingonlymildstress.CoronaG,RastrelliG,BartfaiG,CasanuevaFF,GiwercmanA,AntonioL,SlowikowskaJ,TournoyJ,PunabM,HuhtaniemiIT,VanderschuerenD,O'NeillTW,WuFCW,MaggiM.Self-ReportedShorterThanDesiredEjaculationLatencyandRelatedDistress-PrevalenceandClinicalCorrelates:ResultsFromtheEuropeanMaleAgeingStudy.JournalofSexualMedicine2021;18(5):908-919.doi:10.1016/j.jsxm.2021.01.187.PMID:33820727.

https://www.jsm.jsexmed.org/article/S1743-6095(21)00241-1/fulltext

Moreevidencesupportingtheworld-widedeclineof semen quality! The systematic meta-analysisreported significant decreases in spermconcentration and total sperm count in 327,373healthy Chinese men between 1981 and 2019,indicatingaseriousreproductivehealthwarning.

Mo-QiLv,PanGe,JianZhang,Yan-QiYang,LiangZhou,Dang-XiaZhou.Temporaltrendsinsemenconcentrationandcountamong327373Chinesehealthymenfrom1981to2019:asystematicreview.HumanReproduction,July2021,36(7):1751–1775.DOI:10.1093/humrep/deab124.PMID:34046659

https://academic.oup.com/humrep/article-abstract/36/7/1751/6287234?redirectedFrom=fulltext

Across-sectionalstudyaimingtoevaluatesemenquality in association with maternal occupationalexposuretopotentialendocrinedisruptersduringpregnancy was carried out among Swissconscriptsbetween2005and2017.Associationswere found for maternal exposure to pesticides,phthalatesandheavymetals(allORbetween1.8and2.2).Thestudyconfirmsthatpregnantwomenshould be informed of potential occupationalhazardthatcouldimpairtheirson’sfertility.MIstvan,RRahban,BDananche,ASenn,EStettler,LMultigner,SNef,RGarlantézec.Maternaloccupationalexposuretoendocrine-disruptingchemicalsduringpregnancyandsemenparametersinadulthood:resultsofanationwidecross-sectionalstudyamongSwissconscripts.HumanReproduction,July2021,36(7),1948–1958,doi.org/10.1093/humrep/deab034

A prospective cross-sectional multi-centre Italianstudyof semenquality in43 sexuallyactivemenwhorecoveredfromCOVID-19.SARS-CoV-2couldbedetectedinsaliva,urine,andsemeninasmallpercentage of these men. One-quarter of mendemonstratedoligo-crypto-azoospermiaindicatingthat an assessment of semen quality should berecommended for men of reproductive age whoareaffectedbyCOVID-19.

GacciM,CoppiM,BaldiE,SebastianelliA,ZaccaroC,MorselliS,PecoraroA,ManeraA,NicolettiR,LiaciA,BisegnaC,GemmaL,GiancaneS,PolliniS,AntonelliA,LagiF,MarchianiS,DabizziS,Degl'InnocentiS,AnnunziatoF,MaggiM,VignozziL,BartoloniA,RossoliniGM,SerniS.SemenimpairmentandoccurrenceofSARS-CoV-2virusinsemenafterrecoveryfromCOVID-19.HumanReproduction2021May17;36(6):1520-1529.doi:10.1093/humrep/deab026.PMID:33522572

https://academic.oup.com/humrep/article/36/6/1520/6125160

COVID-19vaccinationdoesnotharmyoursperm!Inthissmallbutreassuringstudyof45volunteerswhoreceived2dosesofeitherPfizer-BioNTechorModernavaccines,spermconcentrationswerenotsignificantlyalteredandactuallyslightly increasedinmostparticipants.

GonzalezDC,NassauDE,KhodamoradiK,IbrahimE,Blachman-BraunR,OryJ,RamasamyR.SpermParametersBeforeandAfterCOVID-19mRNAVaccination.JAMA2021,Jun17.doi:10.1001/jama.2021.9976.Epubaheadofprint.PMID:34137808.CommentonCNN:https://edition.cnn.com/2021/06/17/health/sperm-count-covid-vaccine-wellness/index.html

Yetanothercohortstudy found that lowerserumtestosterone concentrations and higher estradiolto testosterone ratios were associated withCOVID-19 severity and circulating inflammatorycytokineconcentrationsinmenbutnotinwomen.Transcriptionalprofilingofcirculatingmononuclearcells revealed upregulation of hormone signalingpathways in patients requiring intensive care vsthosewithmilderdisease.Butcautionshouldbepracticed with approaches that antagonizetestosteronesignalingorsupplementestrogentotreatmenwithsevereCOVID-19.

DhindsaS,ZhangN,McPhaulMJ,WuZ,GhoshalAK,ErlichEC,ManiK,RandolphGJ,EdwardsJR,MuddPA,DiwanA.AssociationofCirculatingSexHormoneswithInflammationandDiseaseSeverityinPatientswithCOVID-19.JAMANetworkOpen.2021;4(5):e2111398.doi:10.1001/jamanetworkopen.2021.11398.PMID:34032853.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780135Commentary:https://medicalxpress.com/news/2021-05-men-testosterone-high-severe-covid-.html

Theoutcomeof ICSIwasstudied inpatientswithazoospermiaorsevereoligozoospermiaandAZFcdeletions. Compared with the control group, theAZFc deletion group exhibited poorer ICSIoutcome,withsignificantlylowerclinicalpregnancyrate, fertilization rate and cumulative live birthdelivery rate. The patients with AZFc deletionshould be informed that they have reducedopportunitiestobebiologicalfathers.

ZhangL,MaoJM,LiM,LianY,LinSL,ChenLX,YanLY,QiaoJ,LiuP.PoorintracytoplasmicsperminjectionoutcomeininfertilemaleswithAzoospermiaFactorcmicrodeletions.Fertility&Sterility2021Jul;116(1):96-104.doi:10.1016/j.fertnstert.2021.01.025.PMID:33745721.

COVID-19

Androgenetics

https://www.fertstert.org/article/S0015-0282(21)00046-7/fulltext

Thisstudy investigatedbyexomesequencing21patientswithseverespermmotilitydisorders,fromArgentina and Australia. In 10 patients (48%),pathogenic variants were identified in knownsperm assembly genes: CFAP43/44/58, QRICH2,DNAH1/H6.Inaddition,thestudyidentifiedvariantsin the novel human candidate sperm motilitygenes: DNAH12, DRC1, MDC1, PACRG, SSPL2CandTPTE2.OudMS,HoustonBJ,VolozonokaL,MastrorosaFK,HoltGS,AlobaidiBKS,deVriesPF,AstutiG,RamosL,MclachlanRI,O'BryanMK,VeltmanJA,ChemesHE,ShethH.Exomesequencingrevealsvariantsinknownandnovelcandidategenesforseverespermmotilitydisorders.HumanReproduction2021Jun5:deab099.doi:10.1093/humrep/deab099.PMID:34089056.

https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deab099/6292397

Amodelexplaininghowacephalicspermatozoainmen with SUN5 mutations ‘lose their heads’ isproposedinthisstudy:SUN5,Nesprin3,andODF1mayforma 'triplet'structureatspermneck.Lossof SUN5 disrupts this structure rendering thehead-tailjunctionfragile.

ZhangD,HuangWJ,ChenGY,DongLH,TangY,ZhangH,LiQQ,MeiXY,WangZH,LanFH.PathogenesisofacephalicspermatozoasyndromecausedbySUN5variant.MolecularHumanReproduction2021;27(5):gaab028.doi:10.1093/molehr/gaab028.PMID:33848337.

https://doi.org/10.1093/molehr/gaab028

The role of TRIM71 in mammalian germ cellembryonic development was studied in agermline-specific conditional TRIM71 knockoutmouse.MaleKOmicedisplayedaSertolicell-only(SCO)phenotype,alreadyapparentatbirth.Exomesequencing analysis identified several TRIM71variantsinacohortofinfertilemen.

Torres-FernándezLA,EmichJ,PortY,MitschkaS,WösteM,SchneiderS,FietzD,OudMS,DiPersioS,NeuhausN,KlieschS,HölzelM,SchorleH,FriedrichC,TüttelmannF,KolanusW.TRIM71DeficiencyCausesGermCellLossDuringMouseEmbryogenesisandIsAssociatedWithHumanMaleInfertility.FrontiersCell.Dev.Biology2021May13;9:658966.doi:10.3389/fcell.2021.658966.PMID:34055789.https://www.frontiersin.org/articles/10.3389/fcell.2021.658966/full

“Sneaky’ sperm particles hitchhike around thebody” (according to a science journalist). Amulticentre collaboration between Australian andEuropean researchers (incl. EAA Academicians)found that germ cell-derived and sperm-specificproteins, includingmultiplecancer-testisantigens(CTA) are deposited by the Sertoli cells of themouse and human seminiferous tubules intotesticular interstitial fluid that is "outside" theblood-testis barrier. Sperm-specific CTA aresignificantly decreased in testicular fluid frominfertile men. The results suggest that theseantigens can possibly be blood-based markersusefulinthemanagementofmaleinfertility.

O'DonnellL,RebourcetD,DagleyLF,SgaierR,InfusiniG,O'ShaughnessyPJ,ChalmelF,FietzD,WeidnerW,LegrandJMD,HobbsRM,McLachlanRI,WebbAI,PilatzA,DiemerT,SmithLB,StantonPG.Spermproteinsandcancer-testisantigensarereleasedbytheseminiferoustubulesinmiceandmen.FASEBJ.2021;35(3):e21397.doi:10.1096/fj.202002484R.PMID:33565176.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898903/

Translationalandbasicandrology

Commentary:https://www.newcastle.edu.au/newsroom/featured/sneaky-sperm-particles

This pilot study compared the taxonomic andfunctional profiles of the gut, semen, and urinemicrobiomes of 25 infertile and 12 healthy fertilemen. The authors identified a diverse semenmicrobiomeandmodestchangesininfertilemen,withanaerobesover-representedinthesemenofmen with a varicocele. Metagenomics dataidentified alterations in the S-adenosyl-L-methionine cycle, which may play a role in thepathogenesisofinfertility.

LundySD,SangwanN,ParekhNV,SelvamMKP,GuptaS,McCaffreyP,BessoffK,ValaA,AgarwalA,SabaneghES,VijSC,EngC.FunctionalandTaxonomicDysbiosisoftheGut,Urine,andSemenMicrobiomesinMaleInfertility.EuropeanUrology2021;79(6):826-836.doi:10.1016/j.eururo.2021.01.014.PMID:33573862.

FunctionalandTaxonomicDysbiosisoftheGut,Urine,andSemenMicrobiomesinMaleInfertility-EuropeanUrologyCommentary:TheMicrobiomeofMaleInfertility:PavingtheRoadAhead-ScienceDirect

A new way to calculate age-dependent ‘fertilityindex’bystandardizedmeasures(Z-scorevalues)ofspermatogonialquantityintissuesamplesfromboyswith cancer andyoungmenwithKlinefeltersyndromewasproposed.Thecellswereidentifiedby morphology and germ cell-specific markers(MAGEA4 and/or DDX4). The Z-score valuesallowed for the quantification of genetic andcancer treatment-related effects on testiculartissue stored for fertility preservation, facilitatingtheiruseforpatientcounseling.

FunkeM,YangY,LahtinenA,Benninghoven-FreyK,KlieschS,NeuhausN,StukenborgJB,JahnukainenK.Z-scoresforcomparativeanalysesofspermatogonialnumbersthroughouthumandevelopment.Fertility&Sterility2021May8:S0015-0282(21)00304-6.doi:10.1016/j.fertnstert.2021.04.019.PMID:33975728.

https://www.fertstert.org/article/S0015-0282(21)00304-6/fulltext

Intheadultmouse,spermatogonialdifferentiationis coordinated by pulses of retinoic acid (RA),presumably acting via retinoic acid receptorgamma (RARG). The authors of this study foundthat RARG alone is insufficient to initiate aspermatogonial response to RA and suggestedthatdifferentialRXRAexpressionmaydiscriminaterespondingcells.

SuzukiS,McCarreyJR,HermannBP.DifferentialRAresponsivenessamongsubsetsofmouselateprogenitorspermatogonia.Reproduction.2021May5;161(6):645-655.doi:10.1530/REP-21-0031.PMID:33835049.

https://rep.bioscientifica.com/view/journals/rep/161/6/REP-21-0031.xml

A new mechanism for how androgen regulatescommunication within prostate cancer cellsdiscovered!Theauthorsfoundcomponentsofanandrogen signaling axis that uses a writer andreader of ADP-ribosylation to regulate protein-protein interactions and AR activity. A key ADP-ribosylation regulatedpathway ismediatedby anenzyme, PARP7, involved in important cellularfunctions,includingDNArepair.

YangCS,JividenK,KamataT,DworakN,OostdykL,RemleinB,PourfarjamY,KimIK,DuKP,AbbasT,ShermanNE,WottonD,PaschalBM.AndrogensignalingusesawriterandareaderofADP-ribosylationtoregulateproteincomplexassembly.NatureCommunications2021May;12(1):2705.doi:10.1038/s41467-021-23055-6.PMID:33976187.

https://www.nature.com/articles/s41467-021-23055-6Commentary:https://www.news-medical.net/news/20210521/New-study-may-lead-to-better-treatments-for-prostate-ovarian-and-breast-cancers.aspx

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