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European Journal of Endocrinology -19-0071 including bothaccidentaltraumaandforceful removal. are vulnerableandeasilyaccessibletomanipulation endocrinology. Thetestes,intheirexposed position, among theearliesttoolsinexperimentalandapplied Extirpation andtransplantationofendocrineglandsare Introduction improved sothatnowphysiologicalserumlevelscanbeachieved. or modificationsofthemoleculehadtobefound.Over85 yearstestosteronepreparationshavebeenslowly use. However,whengivenorally,testosteroneisinactivatedintheliver,sothatparenteralformsofadministration well asLeopoldRuzicka(Zürich)synthesizedtestosterone.Sincethentestosteronehasbeenavailableforclinical detours togetherwiththeirteamsin1935,ErnstLaqueur(Amsterdam)isolatedandAdolfButenandt(Gdansk)as century scienceandtheyoungpharmaceuticalindustryinitiatedsearchformalehormone.Afterseveral scale, althoughthesepracticeshadonlyplaceboeffects.Inreactiontosuchmalpracticeinthefirsthalfof20th Testes wereusedinorganotherapyandtransplantedastreatmentforsymptomsofhypogonadismonalarge servants, forpunishment,preservationoftheprepubertalsopranovoiceandeventreatmentdiseases. identified astheactiveagent.Practicalapplicationsofthisknowledgewerecastrationmalestoproduceobedient biological effectsoftestosteroneandthetesteshavebeenknownsinceantiquity,longbeforewas As themostimportantmalehormone,testosteronehasanimpactonalmostallorgansandbodyfunctions.The Abstract Centre ofReproductiveMedicineandAndrology,UniversityMünster,Domagkstr.11,Germany Eberhard Nieschlag development oftestosteroneforclinicaluse The historyofdiscovery,synthesisand ENDOCRINE HISTORY https://doi.org/ https://eje.bioscientifica.com Review and awards,heisalsotherecipient oftheGermanFederalCross ofMerit. president oftheEuropeanSociety ofEndocrinology. memberships Inadditiontoseveralhonorary the ageing male, male contraception and doping. Prof. Nieschlag has beenthe second research activitiesfocusonreproductiveendocrinology andandrology, testosteronesubstitution, Reproductive MedicineandAndrologyoftheUniversity ofMünster, Germany. Hisclinicaland Prof. Drmed.h.c.EberhardNieschlagFRCP Invited Author’s profile 10.1530/EJE -19-0071 and Susan Nieschlag 6 © 2019EuropeanSociety ofEndocrinology E NieschlagandS Printed inGreatBritain isanemeritusprofessorattheCenterof and theirfunctioninthe17th18thcentury, and ofsperm since antiquityandlongbeforethediscovery of lossthetestesortesticularfunctionwereknown only byphysiciansbutalsolaymen,sothattheresults Loss ofvirilityandfertilityareeasilyrecognizable,not History oftestosterone Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at10/02/202103:13:32PM (2019) Endocrinology European Journalof ukmuenster.de Eberhard.Nieschlag@ Email to ENieschlag should be addressed Correspondence 180 180 :6 , R201–R212 ,

R201 –R212 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com him becastrated’. hanged foranyfault,butlet hiseyesbeputoutandlet and blinding:‘Ialsoforbid that anyoneshallbeslainor Anglo-Saxon deathpenalty and replaceditbycastration France. After1066,William theConquerorabolished legislation wherevertheyruledforexampleinSicilyand which was adopted by theNormans who introduced this punishment, buttocastrationcombinedwithblinding, In Scandinaviahightreasonwasnotsubjecttocapital formed elitetroopsdeployedinwarsofconquest. In Islamicsocietiesoverthecenturiescastratedslaves eunuch, SunYaoting, diedin1996attheageof94 years. among therichestpersonsinhistory. Thelastimperial oceans, orLinYin (1451–1510), who isstillcounted expeditions intocountriesaroundtheIndianandPacific by AdmiralZhèngHé(1371–1435),leaderofsevenlarge eunuchs obtainedhigh-rankingpositions,asexemplified dynasty (1368–1644),attheChineseimperialcourt, their masters and rulers. As documented since the Ming castration was used to produce obedient slaves, loyal to However, evenbeforethiswrittendocumentation, and described its consequencesinanimalhusbandry. knew theeffectsofcastrationinmenaswellanimals generation ofvisibleorgansinfertilizedchickeneggs.He The GenerationofAnimals andwrote philosopher oftheHellenisticera,observed Aristotle (384–322 B.C.), the universalgenius and Consequences ofcastration of testosteronepreparationsforclinicalusefollows. in successfulcooperation;anaccountofthedevelopment industrial enterprise to isolate and synthesize and organotherapy challenged academic research and century, thehypesurroundingtestistransplantation over centuries, before, at the beginning of the 20th this knowledgewastranslatedintopracticalapplications known aboutthephysiologicalroleoftestesandhow so longandconvoluted,wewillbrieflydescribewhatwas In ordertounderstandwhytheroadtestosteronewas of testosteroneandtriestoexplainthismisunderstanding. not completelycorrect.Thisarticledealswiththehistory have beenhonouredbyaNobelPrize;thisassumptionis andsynthesisofthisimportanthormonemust discovery present-day endocrinologistsoftenassumethatthe ( and synthesized in the 20th century long beforetestosterone,astheactiveagent,wasisolated Review Castration was also applied as lawful punishment. inwhichhedescribedthe E NieschlagandS 1 ). Although even illegal operation,forbiddensince1587byPopeSixtusV. the tradethereguaranteedutmostsecrecyconcerningthis 13th century, andthe30familydynastiesmonopolizing onyoungboys,goingbacktothe specialized insurgery school inthemiddleItaliancitiesofNorcia andPreciwere so thathisvoicecanstillbeheardtoday( bygramophonerecordingsin1902and1904 preserved to singintheSistineChapelandhisperformancewas of protectionagainstcholera,becamethelastcastrato who wascastratedattheageof9 years underthepretence early 20th century. Alessandro Moreschi (1858–1922), the Vatican choirsthesevoicescouldbehearduntilthe (1705–1782) orDomenicoAnnibaldi(1705–1779).In castrates becamefamoussoloists,suchasCarloFarinelli in operasthe17thand18thcenturies.Someofthese acoustic volumeofanadultmaleresultandwerefeatured voice ofboyssothatsopranoandaltovoiceswiththe was knownthatprepubertalcastrationmaintainsthehigh allow himtofightforrecognition ofhisfindings( his opinionprevailedandBerthold’s personality didnot rubbish ( to repeattheexperiments,but failedanddeclaredthemas of Göttingen,RudolfWagner (1805–1864),wasjealous, tried Endocrinology’. However, Berthold’s rivalattheUniversity and is therefore widely recognized as the ‘Father of effect ofthe testes on distant organs as a general principle a whole’( suitable ensuingactionofthebloodonorganism as through theiractionontheblood,andthen the productiverelationshipoftestes,thatistosay, Berthold concludedthattheseeffects‘mustbecausedby roosters andshowedanormalinclinationtohens’. often foughtamongthemselvesandwithotheryoung androgenic functions:‘Theycrowedquiteconsiderably, that testestransplantedfromroosterstocaponsrestored Göttingen, ArnoldAdolphBerthold(1803–1861)observed other. AsphysicianandphysiologistattheUniversityof of experimentalendocrinology, replacingglandsisthe While removalofendocrineglandsisonebasictool Proof ofendocrinefunctionthetestes rather thelackofknowledgerespectiveperiod. masturbation andinsanity( the treatmentofleprosy, epilepsy, gout,priapism,excessive purposes duringGreek-RomantimesandtheMiddleAgesfor History oftestosterone Deliberate mutilation also served otherpurposes. It Deliberate mutilationalsoserved Castration was also recommended for therapeutic Castration wasalsorecommendedfortherapeutic 5 4 ). Ashebecamethefullprofessor ofphysiology, ). He was thus the first to postulate a humoral ). Hewasthusthefirsttopostulateahumoral Downloaded fromBioscientifica.com at10/02/202103:13:32PM 3 ), reflecting the knowledge or ), reflectingtheknowledgeor 180 :6 2 ). Themedical 6 ). R202 via freeaccess European Journal of Endocrinology heart attackssoonthereafter. compensation. Brinklydeclared bankruptcyanddiedof a seriesoflawsuitsdemanding millionsofdollarsas guilty ofactingasacharlatan andquack,thusunleashing and 1930.However, in1939 a Texan judge found him Milford, Kansas,intoaboomingbusinessbetween1918 medic, turnedgoattestistransplantationinhisclinic in on thepartofpatients,including13physicians( sources for his testicular grafts and reported satisfaction reported signsofrevitalization.Laterheturnedtorams as of testesfromexecutedprisonerstootherinmateswho Quentin, reportedin192320casesoftransplantation Stanley (1886–1976),attheCalifornia State PrisonSan from donorstopatientsforrejuvenation( in 1913hisexperiencewithtransplantinghumantestes Also in Chicago Victor D. Lespinase (1878–1946) published transplantation from accidentvictims to recipients ( 1915 wasoneofthefirsttoperformhumantesticular (1858–1923) at Cook County Hospital in Chicago therapy forallsortsofdisorders.GeorgeFrankLydston to treathypogonadismandbringaboutrejuvenation ( Probably promptedbytherevivalofBerthold’s experiments Berthold’s experiments Erroneous conclusionsfrom actually duetotheinterstitialgland( organism, ascribedinthepasttotestesasawhole,is hypothesis: thatthegeneralactionoftesteson that, takentogether, allowustoformulatethefollowing group ofmorphological,physiologicalandchemicalfacts ‘In numerouspreviousstudieswehaveassembleda conclusions fromextensiveexperimentationasfollows: function totheLeydigcellsbysummarizingtheir Ancel and Bouin ( Berthold’s originalresults in cocks in 1911 ( in rats1910( in frogs1909( repeated Berthold’s experimentsandconfirmedtheresults Nussbaum (1850–1915),professorofanatomyinBonn laterwhenMoritz acknowledged onlyhalfacentury and importance( species, however, withoutunderstandingtheirfunction described theinterstitialLeydigcellsintestesofmany Leydig (1821–1908)attheUniversityofWürzburg 1 Review ), surgeonsturnedtotestestransplantationasameans John RomulusBrinkly(1885–1942)ahalf-educated Berthold andhisresearch wererehabilitatedand Incidentally, atthesametimeanatomistFranz 9 ). Finally, A.PézardinParisconfirmed 7 ). 8 11 ), asdidEugenSteinachinVienna ) clearly attributed an endocrine E NieschlagandS 12 )’. 14 10 ) andLeo ). Earlier 15 13 ). ). finally terminatedthequestionablebusinessoftestes male sexhormone,followingthatoffemalehormones, andsynthesisofthe would ultimatelyleadtothediscovery declaring Voronoff’s claimsaspoppycock. Algiers. Thecommitteeconcludedtheirinvestigationsby (London) sentaninternationalcommitteetoVoronoff in this quackery, in1927theRoyalSocietyofMedicine unrest among the medical profession grew concerning pieces thereoftopatientsdemandingrejuvenation.When Voronoff’s followersxenotransplantedanimaltestesand by patientsfromallovertheworld.Inmanycountries, questionable operationsinAlgiers,wherehewasvisited inParis,butaftersomescandalscontinuedhis his surgery to be transplanted for rejuvenation ( turned toxenotransplantationandusedmonkeytestes ( surgeons toperformunilateralvasoligationforrejuvenation minute amounts of testosterone, as we could determine other components,alsocontains 1920s andmarketeduntiltoday isOkasa and yohimbin.Anotherfamous preparationfromthe impotence ( became afinanciallysuccessfuldrugfortreatment of up intothe20thcentury. Inthe1920sTestifortan continued tobemanufactured,prescribedandconsumed testes inwineasavehicle( the tasteofhisprescription,recommendedpowderedhog Cologne, AlbertusMagnus(1192–1280),concernedwith The ‘UniversalDoctor’andfounderoftheUniversity of Hsue Shu-Wei prescribedrawanddesiccated testes. extracts. AlsoinChinesemedicine–atleastsince1132 – Mesue theElder(777–837)inBaghdadrecommendedtestis and impotence.ForthesamepurposeArabicphysician testes forthetreatmentofsymptomshypogonadism Secundus ( various modalities.EarlyoninRomeGaiusPlinius and healerstoturntheingestionoftheseorgansin the testesinnormalmaleorganisminducedpatients Since antiquitytheknowledgeofpowerfulfunction Testes fororganotherapy needs tobediscussed. medicalmisapprehension opened, anothercentury-long and can be testosterone biochemistry transplantation. However, beforethechapterofmodern History oftestosterone 16 ). Oneofhisfollowers,SergeVoronoff (1866–1951) Similar preparations,butnowintabletform, These scandals and the hope that steroid biochemistry These scandalsandthehopethatsteroidbiochemistry In Vienna, EugenSteinach (1861–1944)convinced 23 19 – 79 ). Itsmainconstituentswere testisextracts ) prescribedtheconsumptionofanimal Downloaded fromBioscientifica.com at10/02/202103:13:32PM 1 , 18 https://eje.bioscientifica.com ). testis sicca 180 17 ). He first offered :6 ® which,among andthereby R203 via freeaccess ®

European Journal of Endocrinology https://eje.bioscientifica.com neurosurgeon, Harvey WCushing(1869–1939),wentso neurosurgeon, Harvey image oftheyoungfield of endocrinology. Thefamous The crazeforsuchproducts causedconcernaboutthe Isolation andsynthesis oftestosterone New York ( as wellinAmerica,forexamplenexttoCentralPark in the (Western) worldandfactoriessprungforth inEurope organs by the Brown-Séquard method’ were sold all over such quackery, because in notimethe‘extractsofanimal at thattimetheworldhadobviouslybeenwaitingfor later( replication oftheexperimentacentury Certainly allthesewereplaceboeffects,asconfirmed by of urineandthepowerdefecationbecamestronger’. with adynamometer, gained6to7 to write apaper on a difficult subject. My limbs,tested experiments forseveralhours.AfterdinnerIwasable I possessedagoodmanyyearsago.wasabletomake took placeinme…Ihadregainedatleastallthestrength onhimself:‘Aradicalchange astonishing observations days made dog or guinea-pig testes daily, and after 20 blood, onepartsemenandjuiceextracted from 1-mL injectionsofamixtureoneparttesticular vein experimentation inthe academies, published the results of his famous self- well-reputed scientist and member of several scientific E Brown-Séquard (1847–1894), who until then was a when,atage72Charles late 19thandearly20thcentury ageing andendocrineobesity’( gonadal insufficiency, impotence,infantilism,premature three decadesofsuccessfulsalesforthetreatment‘male gonads’ fororalandparenteraluse)onlyin1961,after Androstin market. Forexample,Ciba(Switzerland)withdrewtheir times whengenuinetestosteronewasalreadylongonthe continued tomanufactureextractsandpillswellinto own effects.Nevertheless,manycompaniesworldwide which,however, maynotbewithoutits administered orallycanonlybeconsideredasaplacebo in theliver( taken orally would be inactivatedbythe first-pass effect testosterone were tobeconsumed, the testosterone in roughly1 production ofanadultmanabout6–8 thyroid orpancreas,donotstoreitsproducts.Thedaily testosterone but,unlikeotherendocrineglandssuchas in the 1970s (unpublished). However the testes synthesize Review Organotherapy literallyexplodedattheendof ® 24 (‘biologicallytitratedfullextractfrommale ). kg of(bull)testes;evenifthisamount 20 ). Therefore,alltesticularorgantherapy Lancet 1889( 21 E NieschlagandS ). kg instrength.Thejet 22 ). Hegavehimself mg iscontained 23 ), but Organization oftheLeague Nations ( Hormones inLondon1932,sponsored bytheHealth International Conferenceonthe StandardisationofSex EA Doisy,AButenandtandGF Marrian attheFirst Figure 1 and reachedaconsensusthatsteroidshadfourrings and GuyMarrianassembledatUniversityCollegeLondon chemists includingEdmundADoisy, AdolfButenandt of Nations(thepredecessorWHO)highlyrecognized the sponsorshipofHealthOrganisationLeague rings, whetherthefourthhadfiveorsixC-atoms.Under three offourringsinthesteroidstructureand,if ( Bavarian AcademyofSciencesinMunichalso1932 Medical Research inLondon1932( of steroidsandbileacidsattheNationalInstitute oftheringstructure breakthroughs werethediscovery replace organotherapybyproperhormonesubstitution. cooperated in ordertorehabilitateendocrinology and and academic researchthe pharmaceutical industry by testiculartransplantationandorganotherapy, this organotherapy. Finallyreactingtothehypegenerated far astotalkabout‘endocri available topatients( organotherapy and tomakeproper steroid substitution ( three furtherteamsaddedprogesteronetothearrayofsex co-operating withscientists.In1934Butenandtaswell pregnant mareurineprovidedbyvariousdrugcompanies Laqueur, hadisolatedpregnandiolandestronefrom before, theseeminentresearchers, includingErnest the fourthringhadfiveC-atoms( History oftestosterone 26 ). Aheateddiscussionensuedwhethertherewere As steroid biochemistry progressed,thegreat As steroidbiochemistry of oestrogenic the structure four ringsin hormones.” “There are 28 ). Their purpose was to replace the miscredited Edward A.Doisy at theDept.ofBiochemistry,UniversityCollegeLondon Table 1 Downloaded fromBioscientifica.com at10/02/202103:13:32PM ) ( mi 29 nology’ inthecontextof ). 89 26 180 ). ) ( :6 25 i. 1 Fig. ) andatthe ). Shortly Guy Marrian R204 via freeaccess European Journal of Endocrinology cooperation. also an early example of successful academic-industrial ( claims worldwideandtoagree onpricingoftheproducts a realcartel/syndicatetoshare knowledge,tostakemarket Roussel (France)andOrganon(TheNetherlands)toform was extended to include Boehringer (Germany), Chimio reluctantly agreed.In1937theCiba-Scheringcooperation their respectiveadvances,towhichtheformerrivals then Technical Universityof Gdansk, toexchange of ZürichandAdolfButenandt(1903–1995)atthe Leopold Ruzicka(1887–1976)attheTechnical University progress and thus forced their academic protagonists started acooperativeefforttoinformeachotherabout (Germany), pharmaceutical companies activeinthefield, in 1935,Ciba(Switzerland)andSchering-Kahlbaum and marketableentity, andafterlengthynegotiation be themorepotent. steroids existedand,ifmorethanone–whichmight the question whether called ‘Androkinin’.Thisbiologicaltesthelpedtoresolve Voss-Test). Thethenstillhypotheticalmalehormonewas under the influence of androgenic substances (Loewe- was basedonregrowthoftheseminalvesicleepithelium and developedthe‘cytologicalregenerationtest’which sex organs biological effects of on the accessory chemical solutions.In1930LoeweandVoss ( of androgenicactivityinbodyproductsaswell comb surface.Thisfirstbioassayfacilitateddetermination measuring androgenicactivityinsquarecentimetersof in 1929establishedthestandardizedcaponcomb’s test under theinfluenceoftransplantedtestes,Moore 1935 Testosterone 1934 1931 1929 Oestron 1929 Oestron 1929 Oestron 1928 Pregandiol Steroid Table 1 1 Review , 21 In thedawnoftestosteroneemergingasabiochemical ofthegrowthacock’sFrom observation comb ). Whileeconomicallyprofitable, thissyndicateis Early isolationofsexsteroids. Ernst Laqueur,PharmacotherapeuticLaboratory, Adolf Butenandt,ChemicalInstitute,Technical Adolf Butenandt,ChemicalLaboratoryUniv. Ernst Laqueur,PharmacotherapeuticLaboratory, Adolf Butenandt,ChemicalLaboratoryUniv. Edward AlbertDoisy,Dept.BiologicalChemistry, Guy FrederickMarrian,Dept.Physiologyand Investigators Univ. Amsterdam University, Danzig Gӧttingen University Amsterdam Gӧttingen St. Louis Biochemistry, UniversityCollegeLondon only one E NieschlagandS or several androgenic 31 ) usedthe et al . ( 30 ) by young policemen from Berlin and which were (androstan-3 Göttingen, isolatedtheandrogenicsteroidandrosterone sequence in1935( respective papersweresubmitted forpublicationinshort vividlyandhowthekey isolation andsynthesisvery protagonists personally, describes the racetotestosterone heads ofresearch atOrganonwhoknewthecompeting less at the same time. Marius Tausk, one of the former explain whythesediscoverieswerepublishedmore or reinforced by the pharmaceutical companies, may testosterone preparation. for 17alpha-,thefirstorallyeffective Ruzicka usedadegradativeapproachwhichhealso Butenandt hadstartedfromdehydroandrosterone,while reproductive physiology. Forthesynthesisof testosterone modern clinicalpharmacologyoftestosteroneandmale synthesis oftestosterone,thusmarkingthebeginning ( of Gdansk,( Butenandt andHanisch( ‘dreadful’ namenorthecompetition,insameyear ‘testosterone’. AlthoughButenandtlikedneitherthis biological testsin1935( which they found to be more active than androsterone in of anotherandrogen,17 From 100 specialized in extracting hormones from animal glands. at theUniversityofAmsterdamandOrganonwere ( Butenandt consideredandrosteronetheprincipal processed byScheringtoobtain15 History oftestosterone 35 ) inZurich/Basel( The closecooperationamongtheresearchers, In 1931AdolfButenandt,thenattheUniversityof Isolated from100 kgbulltestesprovided Isolated from50,000sowovaries, Extracted from15,000 Lurineprovided Benzol extractsfrompregnantmare Raw extractsandcrystalsfrompregnant From urineofpregnantwomen Crystalline materialfrompregnantmare Source ofmaterial by ORGANON extracts providedbySCHERING Berlin andprocessedbySCHERING by thePrussianPoliceAcademyin providedbyORGANON mare urineprovidedbySCHERING HOUSES urine providedbyBRITISHDRUG kg ofbulltestestheyextractedandisolated10 32 α ). ErnstLaqueur(1866–1947)andhisgroup i. 2 Fig. -ol-17-one) from15,000 36 ) aswellRuzickaandWettstein ). i. 3 Fig. Downloaded fromBioscientifica.com at10/02/202103:13:32PM 33 34 ). Theybaptisedthishormone β ) atthattimetheUniversity -hydroxy-4-androstene-3one, ), publishedthechemical https://eje.bioscientifica.com mg ofthissubstance. 180 L ofurineprovided :6 Reference ( ( ( ( ( ( ( 32 27 31 87 86 85 84 R205 ) ) ) ) ) ) ) mg via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Company andwashonoured forhisinventionofthe Gerhard Domagk(1894–1964) whoworkedattheBayer by theLaureatefor Nobel PrizeforMedicine, the prizemoneymustbecollectedwithinayear. medal, butnotthemoney, sinceaccording to thestatutes, Butenandt receivedtheNobelPrizediplomaand regime. In1949,attheSwedishConsulateinFrankfurt, von Ossietzky, ajournalistandstrongopponent ofthe 1937, theNobelPrizeforPeacehadbeenawardedtoCarl forbidden GermanstoaccepttheNobelPrizeafter, in the NaziregimefromacceptingprizesinceHitlerhad Wilhelm-Society inBerlin1936;hewaspreventedby oftheKaiser- director oftheInstituteforBiochemistry prize ceremonyinStockholm.Butenandthadbecome explicitly fortestosterone! on polymethylenesandhigherterpens’alsonot – butnotfortestosterone!)andRuzicka‘forhiswork hormones’ (oestrogen,progesteroneandandrosterone jointly,Prize for chemistry Butenandt ‘for his work on sex described byButenandtandHanischin1935( Synthesis oftestosteronefromdehydroandrosteroneas Figure 2 O O Review Incidentally, in 1939 the sameindignity was suffered Nevertheless, neitherlaureatecouldattendthe In 1939ButenandtandRuzickareceivedtheNobel Androsterone Testosterone CH CH 3 3 CH CH 3 3 O OH HO 35 2 androsterone A 4 1 Dehydro- CH 3 6 CH E NieschlagandS 3 17 O HO HO O 35 2 A 4 1 34 CH CH CH ). 3 3 3 6 CH CH CH 3 3 3 17 O·CO·CH O·CO·CH OH 3 3 in 1935( methyltestosterone asdescribedbyRuzickaandWettstein Degradative synthesisoftestosteroneand17alpha- Figure 3 ended, Ruzickadelivered his NobelPrizelectureon Baron HGBeck-Friis( to RuzickabytheSwedish ambassadorinSwitzerland, special ceremonyinZ War 16,1940–well withinayear–at II,onJanuary because of turmoilcaused by the beginning of World Kaiser-Wilhelm-Society), from1960to1972. serving became presidentoftheMax-Planck-Society(theformer war, hisresearch concentratedoninsect hormonesandhe ( author’s institutionalstreetaddressisnamedafterhim.) at theUniversityHospitalsinMünsterandtherefore had startedhisacademiccareerbetween1925and1929 reason asButenandt–nomoney. (Bytheway, Domagk from theSwedishKinginStockholm,but–forsame and onlyin1947receivedtheNobelPrizedocuments even imprisonedforafewdaysacceptingthehonour first clinically usedsulfonamide Prontosil®.Domagkwas History oftestosterone O 37 4-andr ). BacktoButenandt, it shouldbenotedthatafterthe As RuzickawasalsonotabletotravelStockholm Andr ost ost er 35 one-3,1 enedione ). 7 -dr one Ac HO O O 17 Ac O -hyd O ro ű xy-4-andr rich, theprizewashanded over Downloaded fromBioscientifica.com at10/02/202103:13:32PM T est H i. 4 Fig. ost H er oste one H ne-3-one ). Afterthewarhad O OCO OCO OH 180 C C 6 6 O H H fr :6 5 5 om cholest Inte 17 α-meth Meth r mediat H ylt H yl-t est erylacetat e deri H est oste R206 oste ve r one d ro

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European Journal of Endocrinology inventory. ( which Ruzickadonatedtothe KunsthalleZürichin1947 FlemishandDutchpaintings collection of17thcentury as royalties ( 1939 aloneCibatransferred56,744SwissFrancstoRuzicka from CibainBaselandtheUSA’. ( my professorialstandard)amountofmoneyasroyalties me during subsequent years an enormous (compared with synthesis oftestosteroneandmethyltestosteroneearned financially rewarding:‘Thepatentsforthedegradative beyond scientificrecognitionhisresearch workwasalso synthesis offragrances. and usedthesamedegradativeapproachasfor synthesis oftestosteroneRuzickastartedfromcholesterol steroids, anotherclassofcyclicalsubstances.Forthe and cooperatedwithhiminthefieldoftriterpenes Ciba was interested in his knowledge of cyclical structures Z attheETHin he becameprofessoroforganicchemistry had tobeextractedfromtheirnaturalsources. In1929 ingredients inperfumeswhichbeforechemicalsynthesis from civettsandsantanolsandalwood,important musk pods(preputialglandsofthedeer),civetone the polycyclical ketones such as muscone, the scent in achievement wasthestructuralanalysisandsynthesisof chemical formulas and synthesis of fragrances. His major (Switzerland) andHolzminden(Germany)toelucidatethe inGeneva he hadworkedintheperfumeindustry could be regarded as a triterpenoid’ ( guided him tosteroids and totestosterone as ‘ research on‘multimembered ringsandhigherterpens’ December 12,1945.Inthislectureheexplainedhow The NobelPrizeDiplomaforLeopoldRuzicka. Figure 4 39 ű Review rich andteamedupwithresearchers atCibainBasel. ) wheretheyformasubstantial partofthemuseum’s As Ruzickaremarkedinautobiographicalnotes, 21 ). Part of this money was invested in a E NieschlagandS 38 ). In the 1920s 39 ). Intheyear which prevaileduntilquite recently andledtocastration some membersofhisfamily. Organon, butwasnotfurtherpersecutedincontrastto his Jewishbackgroundandhadtosurrendersharesin Netherlands in1940,Laqueurlosthispositionbecauseof Dutch nationality. WhentheGermansinvadedThe for thetreatmentofdiabetes.In1930Laqueuracquired Organon became the first European producer of (The Netherlands)toextractinsulinfrompigpancreas. Organon locatednexttotheslaughterhousesinOss at theUniversityofAmsterdam.In1923heco-founded Germany. In 1920 he became professor of pharmacology and receivedhismedicaleducationdegreesin up nearBreslau(Silesia),atthattimestillinGermany 1939 remainsunclear. Laqueurwasbornin1880andgrew hormone wasnotrecognizedbytheNobelCommitteein than androsteroneasthemostimportantmalesex about testosterone influencing prostate carcinoma ( Around thesametimeHuggins alsopostedhiswarning Early warningfortestosterone receptor orandrogenmutations. – ofcoursewithoutknowinganythingabouttheandrogen ‘testicular feminisationinmalepseudo-hermaphroditism’ first casesofcompleteandrogeninsensitivity(CAIS) as carries hisnametodateandMorris( a syndromewithpartialandrogeninsensitivity(PAIS) that Sertoli-cell-only syndrome.Reifenstein( ( discussion that continues until today. Del Castillo termed as ‘male climacteric’ ( described systematically, butunfortunatelyincorrectly at thattimethesymptomsofageingmalewerefirst of testosterone,butwithactivespermatogenesis.Also eunuch syndrome,characterizedbyallsymptomsoflack 1944 ( syndrome in1942( werefirstdescribed,thatistheKlinefelter andsecondary possible, thatmajorsyndromesofprimary for clinicaluse,thatis,whenrationaltreatmentbecame at thesameperiodwhentestosteronebecameavailable heightened interestintheclinicsofhypogonadismthat It maynothavebeenacoincidence,butsignof New syndromesofhypogonadism History oftestosterone 44 ) published in1947 the first five cases suffering from Why Laqueur’s identificationoftestosteronerather 41 ). PasqualiniandBur( 40 ) andtheKallmannsyndromein Downloaded fromBioscientifica.com at10/02/202103:13:32PM 43 https://eje.bioscientifica.com ), starting a controversial 42 ) describedthefertile- 180 46 45 :6 ) publishedthe ) firstdescribed R207 t al et 47 via freeaccess ), . European Journal of Endocrinology https://eje.bioscientifica.com androgens. In errorsomephysicians considered higher doses( it waslivertoxic,especially underlong-termuseorat for clinicaluse( against degradationintheliver, itsoon waswellaccepted effectiveness. Sincethe17 17 testosterone Ruzicka long toreachthesegoals. possible ( physiological serumtestosteronelevelsasclosely as could be determined, an additional goal was to mimic hypogonadism. Later, whenserumlevelsoftestosterone preparations for clinical use was to optimize treatment of major goaloftheeffortstoproducenewtestosterone is referredtoareviewbyBehreandNieschlag( preparations androutesofadministrationthereader For amorecompletedescriptionofthemanytestosterone 3. 2. 1. problem: the liver. Three approaches were used to overcome this inactivation oftestosteronebythefirst-passeffectsin we knowthatthelackoforaleffectivenessisdueto were simplynotavailableand/ortooexpensive.Today know today–wouldrequireextremelyhighdoseswhich doses, testosteronewasnoteffectiveorallyor–aswe Soon afteritssynthesisitbecameclearthat,inreasonable for clinicaluse( Development oftestosteronepreparations deficiency afterradicalprostatectomy andcastration( even consideredforpatientssufferingfromtestosterone testosteronetreatmentis under carefulsupervision ( serum testosteronelevels( Only recentlyitbecameclearthatneitherendogenous treatment inmanypatientswhomighthaveneededit. especially amongurologists,whichpreventedtestosterone injections’ induced a general fear of testosterone, statement ‘Canceroftheprostateisactivatedbyandrogen or antiandrogenswasintroducedinstead.Huggins’ androgen deprivationtherapy(ADT)byGnRHanalogues as themajortreatmentofprostatecarcinoma, when 49 Review α ) have an impact on prostate carcinogenesis. Nowadays -methyl-testosterone andhaddemonstrateditsoral molecule. esterification inposition17 parenteral applicationand Chemical modificationofthesteroidmolecule, As mentionedabove,in1935togetherwith 52 ). Asshownintheensuingtext,ittookquite 55 ), afeaturesharedbyall17 54 ). However, duetoits17 1 ) t al et 48 ) nortestosteronetreatment . ( α -configuration protected E NieschlagandS 53 β ofthetestosterone ) hadsynthesized α substituted α -structure 51 ). A 50 ). for intramuscularinjection.Testosterone propionatewas the 17 making testosterone clinically effective is esterification at substitution purposes.Therefore,thethirdpossibilityof half-life ofonly10 sporadically stillusedtoday( may providesubstitutionforuptohalfayearandare extrusion. However, if enough pellets are implanted, they small operationandharbourstheriskofinfection pellets arestillinusetoday. Theirapplicationrequiresa pellet implantswerethefirsttobeinvestigated( parenteral routeswereexplored.Subdermaltestosterone testosterone undecanoateinthelate1970s(seebelow). for clinicaluseafterintroductionoforallyeffective least inEurope,17 thus makingtestosteroneadangerousdrug.Eventually, at toxicity ageneral feature of testosterone preparations, predominantly erythropoietic, osteogenicoranabolic predominantly erythropoietic, in order to disentangle the various effects and produce tried tomodifythechemical structureofthemolecule been revivedfortreatmentof hypogonadism( nasal routehasalsobeenexplored( compliance theyhaveneverpenetratedthemarket.The applied twice daily ( on thegingivaandresultingineffectiveserumlevels if this areaarebioadhesivebuccaltestosteronetablets,placed commercially available. A more recent development in rather unpredictable serum levels( weremarketedbyFerring( of thesteroid’s duringwhichtestosterone history modern preparations. still usedtodayasacost-effectivealternativetomore andis substitution ofhypogonadismforhalfacentury this remainedthemajortestosteronepreparationfor swings inmood,activityandlibidobetweeninjections, normal. Althoughpatientsdonotappreciatetheseuneven followed byslowdeclinetolevelsbelowthelowerlimitof by transientsupraphysiologicalpeaksforafewdays, ( in 250 marketed asintramuscularTestoviron was synthesizedbyJunkmann( effective serumlevelsarereachedforonly1–2 days. in 1936.However, thisesterhasashorthalf-lifesothat the firstoftheseestersmarketedbyCibaandSchering History oftestosterone 58 ). However, thepharmacokineticsarecharacterized When injected,testosteronehasanextremelyshort As nativetestosteroneprovedtobeineffectiveorally, In the 1950s to 1970s, the pharmaceutical industry In the1950sto1970s, pharmaceuticalindustry Other parenteralroutesweretestedinthecourse Following thepropionateester, testosteroneenanthate β gdss rvdn usiuinfr23 weeks mg doses,providingsubstitutionfor2–3 -hydroxy groupofthemolecule,makingitsuitable α -methyl-testosterone becameobsolete min andassuchisnotsuitedfor 60 ). However, due to low patient Downloaded fromBioscientifica.com at10/02/202103:13:32PM 51 ). 58 57 61 180 ) and are nolonger ) atScheringand ® ) andhasrecently Depotinjection :6 59 ), butyielded 62 ). 56 R208 ) and via freeaccess European Journal of Endocrinology silastic implants, delivering the active substance for a rather short half-life, it was administered via subdermal thereby have little effect on the prostate. As MENT has a have theadvantageoflacking conversiontoDHTand androgen formalecontraception. Thisandrogenmight 7 widely usedforthetreatmentofhypogonadism. testosterone undecanoateasdescribedbelowandisnow male contraception,WHOswitchedtointramuscular further ( could be persuaded to develop this promising preparation substitution ( male contraception – and by the same token, also for identified as a long-acting preparation, well suited for WHO, was synthesized ( acting testosterone preparations. Under theauspices of both organisationsstartedprogrammesinsearch oflong- of clinicaltrialssee( preparations requiredtoofrequentapplications(forreview for generaluse.However, theexistingtestosterone time –andremainssotodatethemostlikelycandidate combination oftestosteroneandaprogestinwasatthat global overpopulation. unmet needforfamilyplanningandasameansagainst Foundation hadidentifiedmalecontraceptionasan as wellthePopulationCouncilofRockefeller despite rathervariableserumtestosteroneprofiles. the late1970s–except in theUSA–andisstillwideuse undecanoate wasintroducedtothemarketworldwidein produce effective serum levels( 3–4 capsuleshadtobetakenduringthedayinorder meal, butthetestosteronepeakswereshort-livedsothat oral testosteroneundecanoatewasbestabsorbedwitha replacement therapy. Initial clinical testing revealed that to thespectrumoftestosteronepreparationsavailablefor avoid thefirst-passeffectinliver( undecanoate, absorbedfromthegutvialymphto potentially causingconsiderableundesiredeffects( shadow existencefordopinginsportsandbodybuilding, evidence-based medicine.However, theyretaineda clinically used,theydisappearedagaininthewakeof while someanabolicandrogenicsteroids(AASs)were the widespectrumoftestosteroneactivities.Nevertheless, to produceandrogenswithonlyonedesiredeffectoutof androgens were synthesized ( steroids. Althoughmorethanathousandofthese α Review -methyl-19-nortestosterone (MENT)asitspreferred Meanwhile, thePopulationCouncilhadturnedto Hormonal male contraception based on the In the1970sWHOHumanReproductionProgram In the1970sorallyeffectivetestosterone 70 ), sothatinitsensuingclinicaltrialsfor 69 ). However, nopharmaceuticalcompany 67 )). To overcome thisdeficiency 63 E NieschlagandS ), it proved impossible 66 ). Oraltestosterone 65 ) hadbeenadded 68 64 ) and ). levels inthenormalrange for several weeks ( in volunteeringhypogonadal menwhoallshowedserum surprisingly long half-life ( brought to Germany, injected into monkeys and showed a across itatameetinginBejing1993( using tea seed oil as a vehicle. When the author came into aninjectablepreparationbyChineseinvestigators provided in oral capsules (see above), had been turned preparation. , originally achieved greatpopularityasarealtestosteronedepot undecaonate preparation entered themarketandsoon but hasnotyetbeenlicensedforthatpurpose. reactionsasitrequiredanalcoholicenhancertodrive testosterone system ( scrotum, preferringasubsequentlydevelopednon-scrotal reluctant toprescribeamedicationbeappliedthe term substitutionrevealed.However, physicianswere with thisphysiologicalpharmacokineticprofile,aslong- satisfied levels could be achieved. Patients were very and, forthefirsttime,physiologicaltestosteroneserum showed excellent pharmacokinetic and clinical results first testedinclinicaltrialsMünster( Virgil Place(1924–2012) at ALZAinPaloAlto(CA)and testosterone preparationinclinicaluse.Inventedby applied tothescrotalskinbecamefirsttransdermal over byanothercompanynotinterestedinthemale. this androgendroppeditsplansinthewakeofbeingtaken the company interested in further clinical research with contraception aswellforsubstitution( year –orperhapsevenlongerthusbeingwellsuitedfor finally acompanycouldbe interestedinthisfascinating application economicallyandecologicallydesirable( non-scrotal applicationisrequired,makingthisformof capacity of scrotalskin, only 20% of the gel needed for for scrotalapplication.Becauseofthehighabsorptive contaminating children or women. It has also been tested shortly after application, thereby reducing the danger of testosterone concentrationcanbewashedofftheskin various gelsavailabletoday, theonewithahigh2.5% by coveringtheapplicationsiteswithaT-shirt. Ofthe against interpersonal transfer have to be taken, mostly almost mimicking the normaldiurnal rhythm. Precautions morning resultinphysiologicalserumtestosteronelevels, upper arms,shouldersorabdomen.Thoseappliedinthe ( testosterone gels in 2000 was welcomed for substitution testosterone throughtheskin( History oftestosterone 76 ). These testosterone-containing gels are applied to the In themid-1990s,transdermaltestosteronefilms Finally, in2004,theintramusculartestosterone For thisreasontheadventoftransdermal 75 ). This,however, causedunpleasant Downloaded fromBioscientifica.com at10/02/202103:13:32PM 79 ), which could be confirmed 1 https://eje.bioscientifica.com ). 180 78 :6 71 ), sampleswere , 73 72 , ). However, 80 74 ). When ), they R209 77 via freeaccess ), European Journal of Endocrinology https://eje.bioscientifica.com the public,commercialornot-for-profit sector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest independent ofexogenoustestosteronepreparations. by feedbacktoLH.Thesepatientswouldthenbecome the transplantedLeydigcellsandwouldbeself-regulated testosterone productionrequiredwouldbeprovidedby system–would bethatthe intact hypothalamo–pituitary ( stem Leydig cells transplanted to hypogonadal patients Ultimately, foridealsubstitutionhoperestsonhuman as performance–enhancingsubstancesandfordoping. authorities. Asunlicensedsubstancestheyareapplied they havebeenlicensedforclinicalusebythedrug the samefateasandrogenicanabolicsteroids,evenbefore actions is required ( hypogonadism, wherethefullspectrumoftestosterone osteoporosis, theywillnotbesuitedforsubstitutionof actions such as required for treatment of sarcopenia or have started, but as theirgoalis selected, testosterone trials forselectiveandrogenreceptormodulators(SARMs) this goal,buthavenotyetreachedperfection.Clinical intramuscular testosterone undecanoate, are close to recent developments, testosterone gels and physiological serumlevelsasrequested( production oftestosteronepreparationsresultingin modalities havebeenimprovedslowlybythe substitution ofhypogonadalpatients.Substitution Since thentestosteronehasbeeninclinicaluseforthe only withinthelasteightdecades,thatis,in1935. the actual molecule itself was isolated and synthesized Although effects of testosterone were known for ages, Outlook in 750 latest approvalwasissuedbytheFDAin2014–however ampoules hasbeenlicensedinover100countries.The 82 weeksofphysiologicalserumtestosteronelevels( 12 could be extended to vehicle and the intervals preparation, tea seedoilwasreplacedbycastoras 84 Review ). Since2004,thispreparationavailablein1000 ). Thegoalforthesepatients–atleastthosewithan mg doses. 83 ). So far, they seem to be suffering E NieschlagandS 52 ). Themost mg 81 , References Publisher, Springer and Heidelberg, forpermissiontocitepassagesfromRef.(1). 3 Fig. reproduce to permission for Stockholm, Foundation, Nobel the (89), 1966 Endocrinology of Journal the from Fig. 1 The authors would like to thank Bioscientifica for permission to reproduce Acknowledgements

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Accepted 5April2019 Received 31January2019

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