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Chapter

1The medical and cultural historyof testosterone and the testesEberhard Nieschlag and Susan Nieschlag

1.1 Introduction 1

1.2 From antiquity to the age ofenlightenment 2

1.2.1 Ancient Egypt 2

1.2.2 Greco-Roman period 2

1.2.3 Castration through the times 2

1.2.4 Power through polyorchidism 4

1.2.5 First description of testicular morphologyand sperm 5

1.2.6 Proof of endocrine function 5

1.3 Detours on the way to modern medicine 6

1.3.1 Organotherapy 6

1.3.2 Testis transplantations 7

1.4 Twentieth-century science and medicine 8

1.4.1 The rise of steroid biochemistry 8

1.4.2 Testosterone is born 8

1.4.3 Early descriptions of syndromes ofhypogonadism 10

1.5 Key messages 10

1.6 References 11

1.1 IntroductionAlthough the term “hormone”was coined only as late as1905 (Starling 1905; Henderson 2005), the biologicaleffects of hormones were known for much longerand probably from the early beginnings of humankind.The over- or underproduction of hormones as the fun-damental pathophysiological principle in endocrine dis-orders often produces phenotypical alterations that canbe easily recognized. Similarly, elimination of hormonesby removing the respective gland or replacing the hor-mones in a deficient organism is a basic tool of experi-mental endocrinology. In their exposed scrotal position,the testes are easily accessible for manipulation, be it byaccidental or by inflicted trauma. The causal relationshipbetween absence of the glands and the resulting bio-logical effects – before or after puberty – is easily recog-nizable, and that is why effects of testosterone, or ratherits absence, have been known from early on. VictorC. Medvei (1993), the master of the history of endocrin-ology, summarized this phenomenon by saying “Theoldest key to the endocrine treasure trove: the testicles.”

Indeed the lack of functional effects of the testes hasbeen noted since antiquity and, in the light of modern

science, these observations are often entertaining fortoday’s reader, but at the same time they are alsoeducational for the medical scholar. In addition, theyreflect the socio-cultural environment of the time whenthey were observed or exploited, so that the history oftestosterone and the testes is not only of medical inter-est, but also of interest to the general public.

The authors of this chapter are not trained histor-ians, but the first author has a keen interest in thehistory of medicine, as documented early by his firstmedical publication dealing with the biography ofOtto Deiters (1834–1863), the describer of the Dei-ters’ cells and nucleus (Nieschlag 1965). While spe-cializing in endocrinology and andrology, historicalevents surrounding testosterone were collected alongwith the scientific studies, culminating in the requestby the Royal College of Physicians (London) in 2005to commemorate the hundredth anniversary of theterm “hormone” by a talk on “The history of testos-terone,” thus precipitating more systematic researchon the subject. Since then a more complete but stillpatchy picture has been developed, which is presentedhere. As it is impossible to give a full history of

Testosterone: Action, Deficiency, Substitution, ed. Eberhard Nieschlag and Hermann M. Behre, Assoc. ed. Susan Nieschlag.Published by Cambridge University Press. © Cambridge University Press 2012.

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testosterone and the testes here, and many develop-ments occurred simultaneously in various epochs, thematerial is summarized under three more or lesssystematic subheadings as follows (1.2–1.4). Never-theless, this is not a systematic review, but rather acollection of historical highlights.

1.2 From antiquity to the ageof enlightenment1.2.1 Ancient EgyptOne of the oldest hypogonadal patients whose imagehas been preserved appears to be Vizier Hemiunu, thearchitect of the pyramid of Giza. The statue in hismausoleum dating from 2531 BC (Roemer-PelizaeusMuseum, Hildesheim) shows a seated man withstraight hairline, no beard, bilateral gynecomastiaand myxedematous lower legs. In contrast, otherstatues from that period show well-built athleticmen; for instance the statue of Amenemhat II(1919–1884 BC) (which travelled in 2011 from theEgyptian Museum in Berlin to be exhibited in theMetropolitan Museum in New York). The plaque onHemiunu’s statue describes his achievements as anarchitect, but does not mention a wife or children aswas customary at the time, indicating that he mayhave been infertile. He could have suffered fromhypopituitarism including hypogonadism, perhapscaused by a prolactinoma, but Klinefelter syndromewould also be a possible diagnosis.

1.2.2 Greco-Roman periodAristotle (384–322 BC), the universal genius and phil-osopher of the Hellenistic era, observed and wrote onThe Generation of Animals, in which he described thegeneration of visible organs in fertilized chicken eggs.He knew the effects of castration in men as well as inanimals, and described its consequences for animalhusbandry. For humans, he developed the fascinatinghypothesis that the right testis produces boys and theleft testis girls. This could be based on case reports ofmen with unilateral anorchia or traumatic loss of onetestis. To date no study could be traced verifying orfalsifying this hypothesis, and a proposed controlledclinical study to be performed today would mostlikely not be met by agreement of an ethics commit-tee. This also demonstrates how misleading casereports may be.

Aristotle also developed a theory of fertilization:semen is the activating agonist of the “soul” fertilizingthe passive female soil. Like his other work, thistheory had a long-lasting effect on science and wasonly superseded by Leeuwenhoek and Spallanzaniabout 2000 years later (see below).

Also dating from the Hellenistic time (about 300BC) until the first century AD, the fertility cultaround Diana/Artemis Ephesina was popular in theentire Greco-Roman world, and was especially pro-moted by the emperors Trajan (53–117) and Hadrian(76–138). This cult had its origin in the temple ofArtemis in Ephesos, the Artemision, where the“magna mater” was worshipped. The statues, of whichan excellent example can be seen in the NationalArchaeological Museum in Naples, are characterizedby multiple oval objects fixed to the goddess’s frontalthorax. Until quite recently these were interpreted asbreasts, but were in reality bull or ram testes whosebearers were sacrificed to the goddess, followingwhich their testes were fixed to the originally woodenstatue, then emanating fertility and potency to theworshipper. This cult is thus based on knowledge ofthe powers of generation connected with the testes.

1.2.3 Castration through the timesIn Greek mythology castration already occurredamong the first generation of gods. Gaea, motherearth, grew out of the chaos and produced Uranosby parthenogenesis, with whom she then generatedthe titan Chronos. When Uranos prevented Gaeafrom creating children with their son Chronos, sheinduced Chronos to castrate his father. This episodehas been depicted beautifully in a fresco by GiorgioVasari (1511–1574) in the Palazzo Vecchio in Flor-ence. Uranos’ testes, thrown into the sea, caused thewater to foam, and out of these bubbles the foam-born goddess of love Aphrodite (= Venus) was born.Quite extraordinary events in terms of reproductivephysiology!

In the real world, castration has been practicedfor socio-cultural purposes since antiquity. Its majorpurpose was to generate obedient slaves who wereloyal to their masters or rulers and who, being infer-tile, could not create competing offspring. Set toguarding harems, they also, and in larger numbers,obtained influential administrative and political pos-itions as in China, and formed elite troops (Mitamura1992; Flaig 2009).

Chapter 1: History of testosterone

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Although most likely already practiced earlier, theearliest documentation of creating eunuchs in Chinadates back to about 1300 BC. The Chinese eunuchsystem, with several thousands at a time, continueduntil the end of the imperial system in 1912. In thenineteenth century there were still about 2000eunuchs at the imperial court in Beijing. The lastChinese eunuch died at the age of 93 in 1996. Onlythe fact that imperial eunuchs could obtain high-ranking positions and considerable power as well aswealth makes it plausible that adult men underwentthis gruesome operation. It was performed by“licensed surgeons” just outside the imperial courtin Beijing, by cutting off testes and penis. About25% of the volunteers did not survive this bloodyoperation. The severed genitals were kept in a box,as shown in the film “The Last Emperor” (1987), andwere eventually buried with their owner.

Eunuchs probably already existed in ancientEgypt. From the times of the legendary QueenSemiramis (about 800 BC) eunuchs were reportedfrom Assyria, and the system developed and con-tinued into the Islamic world in the Middle East andNorth Africa. Over centuries, slaves were deportedfrom Sub-Saharan Africa to the Islamic cities andcourts, and many of the slaves who survived theexhausting march through the desert were then cas-trated to serve as laborers, guards, administrators andeven soldiers (Barth 1857). It is astonishing that thesetasks could be fulfilled without the anabolic effects oftestosterone.

It has been estimated that the transatlantic deport-ation of Africans to the Americas between 1450 and1870 comprised about 11.5 million people, while theentire Islamic deportation of slaves from Africabetween 650 and 1920 amounted to 17 million people,and several million of these African slaves were cas-trated. This constant drain of manpower effectivelyprevented economic and cultural development ofSub-Saharan Africa. In medieval times slaves werealso exported from Europe to the Islamic countries.These slaves were mainly from Eastern European(Slavic) and Central Asian countries. There werewell-established slave routes through Europe, andVerdun has the questionable historical fame of havingbeen the European center for castration of slaves ontheir way from the East to the South at those times(Flaig 2009).

Castration has also been practiced as lawful pun-ishment. In medieval Scandinavia, castration

combined with blinding was administered for hightreason, especially when the insurgent was a closerelative whom one did not want to kill directly. Astold in the Islendinga Saga, Sturla of the SturlungarClan in Iceland castrated and blinded his rebellingrelative Oraekja Snorrason in 1236 (personal commu-nication from U. Ebel, Chair of ScandinavianSciences, University of Münster, 2007). When theNormans migrated south they also introduced thispenal practice in the areas they invaded. When heestablished his reign in Britain after 1066, Williamthe Conqueror abolished the Anglo-Saxon death pen-alty and replaced it by castration and blinding: “I alsoforbid that anyone shall be slain or hanged for anyfault, but let his eyes be put out and let him becastrated” (Van Eickels 2004). As a further example,in Sicily in 1194 King William III was castrated andblinded after a rebellion against Emperor Henry VI.This episode forms the historical background forKlingsor’s castration in the Parsifal epos (Tuchel1998). The Toulouse Law Codex of 1296 described(and depicted) castration for high treason.

Throughout the centuries, castration was appliedto beaten enemies by victorious soldiers for revengeand as a measure to eliminate the enemies withoutoutright killing. When Italian troops invaded Ethiopiaand lost the battle of Aduwa in 1896, supposedly 7000Italian soldiers were castrated (Melicow 1977). Asreported by Babtschenko (2007), this still happenedon both sides during the Chechen War in theCaucasus in 1996.

Castration has also been reported as self-mutila-tion for religious reasons since ancient times in orderto make a life of chastity easier. The early churchfather Origines (186–254) is one of the most promin-ent examples. In the eleventh to fourteenth centuriesthe sect of the Catharers, with their strongholds inSouthern France, promulgated self-castration as partof a “pure” life. More recently, castration was prac-ticed in Southern Russia among members of theScoptic sect founded in the eighteenth century, andthe medical consequences were documented (Wilsonand Roehrborn 1999). The largest contemporarygroup of castrates are the hijras in India. They func-tion as professional well-wishers at birth rites, andreceive considerable financial rewards. Several thou-sand of them exist.

Castration has also been used as revenge forseduction and adultery through the centuries. Forexample, Paris has been reported to have castrated


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Peritanos after he had seduced his famous wifeHelena (Lehrs 1832). The case of the great medievaltheologian and philosopher Peter Abaelard (1079–1142) has been celebrated in history and literature.As master of the cathedral school in Paris he seducedone of his disciples, Heloise (1100–1164), whose unclethen had Abaelard castrated by paid criminals. Des-pite the lack of testosterone, one of the most romanticlove stories documented by literature developed(Podlech 1990). This type of revenge continues intomost recent times as demonstrated by an incident inGermany in 2011 when the father of a 17-year-old girlcastrated her 57-year-old lover (Holzhaider 2011).These people had migrated to Germany from Kazakh-stan and might have brought rules of self-justice withthem.

Castration before puberty maintains the highvoice of boys, so that soprano and alto voices withthe acoustic volume of an adult male result. Suchhigh-pitched voices were considered desirableamong music lovers, especially at times whenwomen were not allowed to sing in church or inoperatic performances. Prepubertal castratesbelonged to casts of operas in the seventeenth andeighteenth centuries; in the Vatican choirs thesevoices could be heard until the early twentieth cen-tury. Some of these castrates became famous soloists,such as Carlo Farinelli (1705–1782) or DomenicoAnnibaldi (1705–1779) (Melicow 1983; Ortkemper1993; Jenkins 1998). The middle Italian city ofNurcia was a center for the operation on young boys.However, most of the thousands of prepubertalcastrates lost their virility in vain as they did notachieve the promised career as a singer, developedonly mediocre voices and were ridiculed by theircontemporaries. An impression of the castrato voice,although of very low recording quality, is preservedfrom the last Vatican castrato, Alessandro Moreschi(1858–1922), in one of the earliest gramophonerecordings, made in 1902 (available today on CD).Today countertenors applying a trained falsetto singthe castrato roles in, for example, Händel operas, buttheir head voices probably only approximate thoseof seventeenth-century castrati. Another impressionof the enormous artistic talents of the castrati isprovided by the recordings of the mezzo-sopranoCecilia Bartoli, who trained her voice to sing theextremely demanding arias by Nicola Porpora(1686–1768), Georg Friedrich Händel (1685–1759)and others (Bartoli 2009).

Prepubertal castration provides an involuntaryexperiment on the influence of testosterone on lon-gevity. A retrospective comparison of the life expect-ancy of singers born between 1580 and 1859 andcastrated before puberty, in order to preserve theirhigh voices, against intact singers born at the sametime, did not reveal a significant difference betweenthe lifespan of intact and castrated singers (Fig.1.1;Nieschlag et al. 1993). This would imply that thepresence or absence of normal male testosteronelevels has no influence on life expectancy.

1.2.4 Power through polyorchidismWhile removal of the testes was used to punish or toweaken the enemy or to obtain specific effects as aconsequence of the lack of testosterone, a super-numerary testis was always considered a sign of extra-ordinary virility and sexual vigor. Several such caseshave been reported anecdotally. The Venetian Con-dottiero Bartolomeo Colleoni (1400–1475), whosesuccess on the battlefield as well as in the bedroomwas legion (Frigeni–Careddu 1996), advertised hisphysical abnormality by showing three testes in hiscoat of arms (“Colleoni” in Italian means “testes”;nowadays spelled “coglioni”).

Allegedly, in 1539 Philipp Magnanimus, Count ofHesse (1504–1567), a protagonist of the Protestantreformation, was granted permission by MartinLuther to have two wives simultaneously: Christinevon Sachsen (1505–1549) and Margarethe von derSaale (1522–1566), because of his three testes.

0

10

20

30

40

50

60

70

80

90

100

Castrates Intact singers

p = 0.65 (non-significant)

Fig. 1.1 Longevity of intact and castrated singers (n = 50 ineach group) born between 1580 and 1859 (matched pairs ofintact and castrated singers with similar birth dates were formed).(Box and whisker plots: solid line = median; broken line = meanvalue) (Nieschlag et al. 1993).


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Because at that time bigamy was forbiddenupon penalty of death, Philipp got in even moretrouble with the Holy Roman Emperor than hisambitions as a religious reformer had caused.A third testis had already been diagnosed in theboy, but without ultrasound, biopsy or post-mortem examination it remains unclear what thesethird structures in his and other famous people’sscrotums were – possibly real testes or large sper-matoceles? Whatever it was, this diagnosis had atremendous impact on the person and on historicalevents.

1.2.5 First description of testicularmorphology and spermThe declaration of the Netherlands as an independentstate during the Thirty Years War (1618–1648), andlegalized at the Westphalian Peace Treaty in Münsterin 1648, resulted in an enormous upswing in econ-omy, culture and science in this country. The medicalsciences also boomed, based on proper research, espe-cially in anatomy, as shown in Rembrandt’s painting“Anatomy of Dr. Tulp” (1632).

The reproductive sciences benefited from thisboom as well. It was Regnier de Graaf (1641–1673)who not only described the Graafian follicle (1672),but also published a book about the anatomy of themale reproductive tract as well as the treatment of itsdisorders (de Graaf 1668). He produced very detaileddrawings and descriptions of the male genital organs,and was the first to discover that the testes werecomposed of a “collection of minute vessels or tubuleswhich confect semen; if these tubules were disentan-gled without being broken and tied to one another,they would far exceed 20 Dutch ells in length.”Having first described this in the edible dormouse,he then went on to the human: a classical case oftranslational medicine. Unfortunately, de Graafbecame involved in a quarrel with his contemporary,Jan Swammerdam (1637–1680), about the question ofwho had first described the follicles, and during thatphase he died under nebulous circumstances at theyoung age of 32 (Setchell 1974).

A few years after Regnier de Graaf’s early andmysterious death, his friend Antoni A. Leeuwenhoek(1632–1723), together with the student Johan Hamm,used his newly invented prototype of a microscopeand described the “little animals of the sperm” in aletter to the Royal Society in London in 1677 (van

Leeuwenhoek 1948). Considering the primitiveappearance of his microscope, the details of his mor-phological descriptions of sperm are amazing, and itis even more amazing that 300 years later we are stillquarreling about normal and abnormal spermmorphology (Kremer 1979).

But it took another century until Lazzaro Spallan-zani (1729–1799), a priest and scientist in Modena,artificially inseminated frogs and dogs and demon-strated the real function of sperm (Spallanzani 1779).By using sperm that he had preserved on ice he alsobecame the father of cryopreservation, without whichmodern reproductive medicine and medicine in gen-eral would be unthinkable.

He was a very systemic investigator and insisted –quite in contrast to others at the time – that experi-ments needed to be repeated before results could beaccepted (Gaeto 1999), a principle that prevails untiltoday.

The anatomist Franz Leydig (1821–1908) inWürzburg described the interstitial cells of the testesin 1850 (Leydig 1850). Although he did not knowtheir function, they still carry his name (Christensen1996). Finally in Milan, in 1865 Enrico Sertoli (1842–1910) discovered the supporting cells in the semi-niferous tubules (Sertoli 1865), also carrying his nameto date (Virdis 2005).

Thus, over roughly two centuries the basic mor-phological elements of the testes had been described,as well as the one major product of the testes, thesperm. Even the function of sperm and fertilizationhad been elucidated, so that the time had come toexplore the basis of testicular endocrine function.

1.2.6 Proof of endocrine functionAlthough the endocrine function of the testes wasknown through their physiological and clinicaleffects, their nature remained completely obscure.While William Harvey (1578–1657) had discoveredthe role of the heart and blood circulation in 1628, insome medical schools Galen’s (AD 129–216 ) conceptof the four bodily humors prevailed well into thenineteenth century. Against this background, it isnot surprising that the idea of a hormone workingas a signal transduced by circulating blood took solong to be born.

John Hunter (1728–1793) is considered by someto be the father of endocrinology, as he transplantedtestes in chickens. However, his outstanding


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achievement as a scientist notwithstanding, hetransplanted testes in order to demonstrate the“vital principle” of living organs. As a surgeon inthe Seven Years’ War (1756–1763), he saw the needfor transplantation of organs and limbs, and this iswhat stimulated his research. He never described histestis transplantations himself, but we learn aboutthem through a scholar, Dr. W. Irvine, in a letter toProfessor Th. Hamilton in Glasgow in 1771:“. . .Nay more, he has many hens just now intowhose abdomen when young, he has put the testesof a cock just separated from his body and his testishas got blood vessels and nerves from the part of theabdomen or viscera to which it is applied. . .” Farfrom any endocrine thought, the goal was to dem-onstrate the survival of the transplant (BarkerJorgensen 1971).

Such thoughts were precipitated by ArnoldAdolph Berthold’s (1803–1861) experiments, whichalso concerned transplanting chicken testes. As pub-lished in 1849, he castrated four cocks: two receivedan ectopic transplantation of one testis, the two othersremained untreated, and he observed “They crowedquite considerably, often fought among themselvesand with other young roosters and showed a normalinclination to hens. . . Since the testes can no longerremain in connection with their original nerves afterbeing transplanted to a strange place. . . it follows thatthe consensus in question must be affected throughthe productive relationship of the testes, that is to say,through their action on the blood, and then throughthe suitable ensuing action of the blood on the organ-ism as a whole.” (Berthold 1849). The paper describesonly four animals and comprises only four pages – incontrast to the extensive style of the time – but wasepochal. However, Berthold’s rival at the University ofGöttingen, Rudolf Wagner (1805–1864) was jealous,tried to repeat the experiments, but failed anddeclared them as rubbish (Wagner 1852). And as hebecame the full professor of physiology, his opinionprevailed. Berthold’s personality did not allow him tofight for recognition of his findings (Simmer andSimmer 1961; Simmer 1980).

As blood circulation, the essential morphologicalelements of the testes and the biological and clinicaleffects of their endocrine action were known, historycould have continued straight from here to the dis-covery of testosterone, but due to these interpersonalquarrels and other unhappy events, further develop-ments took an oblique route.

1.3 Detours on the way to modernmedicine1.3.1 OrganotherapyAs it was known that removal of the testes caused theclinically evidenced symptoms of hypogonadism,including impotence, prescribing ingestion of testesto remedy the symptoms was a medical reflex inher-ent in organotherapy, practiced since antiquity. Thusthe Roman Gaius Plinius Secundus (AD 23–79) rec-ommended the consumption of animal testes to treatsymptoms of testosterone deficiency. Slightly morerefined was the prescription of testicular extracts forthe same purpose in Arabic medicine, for example byMensue the Elder (777–837) in Baghdad. Also, inChina, raw and desiccated testes were prescribed,documented at least in the twelfth century by HsueShu-Wei. Around the same time, Albertus Magnus(1193–1280) in Cologne, better known as a philoso-pher, recommended powdered hog testes, but refinedhis recipe by offering the powder in wine (Medvei1993).

Since early documentation, these potions con-tinued to be prescribed and consumed up intothe twentieth century. In the 1920s Testifortan®became a financially successful drug for treatment ofimpotence (Hirschfeld 1927). Its main constituentwas testis extracts and yohimbine, and after the war17a-methyltestosterone was added without changingthe name. Another famous preparation from the 1920sand still marketed today is Okasa® which, among othercomponents, also contains testis sicca and therebysmall amounts of testosterone, as we could determinein the 1970s (unpublished data). However, as the testessynthesize testosterone but do not store it, the dailyproduction of an adult man of about 6–8 mg iscontained in roughly 1 kg of (bull) testes, and even ifthis amount of testosterone were to be consumed, thetestosterone taken orally would be inactivated by thefirst-pass effect in the liver (Nieschlag et al. 1977).Therefore, all testicular organ therapy administeredorally can only be considered as a placebo medication,which, however, may not be without its own effects(Bundesärztekammer 2011). Ultimately this type oftesticular organotherapy was terminated by the adventof phosphodiesterase inhibitors.

Organotherapy literally exploded at the end of thenineteenth century when Charles E. Brown-Séquard(1847–1894), who until then was a well-reputed


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scientist and member of several scientific academies,published the results of his famous self-experimen-tation in the Lancet (Brown-Séquard 1889). He gavehimself 1-ml injections of a mixture of one parttesticular vein blood, one part semen and one partjuice extracted from dog or guinea-pig testes daily,and after 20 days made astonishing observations onhimself: “A radical change took place in me. . . I hadregained at least all the strength I possessed a goodmany years ago. I was able to make experiments forseveral hours. After dinner I was able to write a paperon a difficult subject. My limbs, tested with a dyna-mometer, gained 6 to 7 kg in strength. The jet of urineand the power of defecation became stronger.”

Certainly all these were placebo effects, but theworld had obviously waited for such quackery,because in no time the “extracts of animal organs bythe Brown-Séquard method” were sold all over the(western) world, and factories sprung forth in Europeas well as in America, for example next to CentralPark in New York (Borell 1976). There must havebeen a real craze for these products, and physiciansconcerned about the image of the young field ofendocrinology started worrying. The famous neuro-surgeon Harvey W. Cushing (1869–1939), and thepresident of the Association of the Study of InternalSecretions, E. H. Rynearson even talked about “endo-criminology” in the context of this organotherapy(Hamblen 1950). This assessment of the medicalscene at the time is also reflected in contemporarycartoons and comic songs from the early twentiethcentury. Eventually, this type of quackery stimulatedscience and decent pharmaceutical companies tosearch for real hormones.

1.3.2 Testis transplantationsHowever, before science succeeded in that attemptthere was another sad approach to treat hypogona-dism and bring about rejuvenation and treatmentfor all sorts of disorders: the transplantation oftestes. G. Frank Lydston (1858–1923) in Chicagowas one of the first to perform human testiculartransplantation from donors after experimentationin animals (Lydston 1915; Schultheiss and Engel2003). V. D. Lespinase (1913) published his experiencewith transplanting human testes to patients for reju-venation, and Leo Stanley (1920) reported 20 cases oftransplantation of testes from executed prisoners toother inmates who reported signs of revitalization.

Later on he turned to animals as sources for his tes-ticular grafts and reported satisfaction on the part ofthe patients including 13 physicians (Stanley 1923).

These surgeons had followers in many parts of theworld, for example even in Iceland where, in 1929, thesurgeon Jonas Sveinsson transplanted testis slicesfrom a poor farmer in need of money to a richNorwegian businessman who, he then claimed, satis-fied his 23-year-old wife so that he even had threechildren with her (Sveinsson 1969). In the SovietUnion, experimentation with human testiculartransplantation continued at least into the 1980s(Shumankov and Gotsiridze 1978). The only testiculartransplantation resulting in fertility of the recipient wasperformed by Sherman J. Silber (Silber and Rodriguez-Rigau 1980) between twin brothers.

In Vienna, Eugen Steinach (1861–1944) per-formed vasoligation for rejuvenation (Steinach1920), and one of his followers, Serge Voronoff(1866–1951) turned to xenotransplantation and usedmonkey testes to be transplanted for rejuvenation(Voronoff 1920; 1923). He first offered his surgeryin Paris, but after some scandals continued his ques-tionable operations in Algiers, where he was obvi-ously visited by patients from all over the world.Voronoff had followers in many countries who xeno-transplanted animal testes or pieces thereof topatients in need of rejuvenation, also in the USA,where this type of treatment caused great interestamong the laymen and the media (e.g. Gayton1922). As unrest among the medical profession con-tinued to grow, in 1927 the Royal Society of Medicine(London) sent an international committee to Voron-off in Algiers, which concluded that Voronoff’s claimswere all poppycock (Parkes 1965). This, and the suc-cess of upcoming steroid biochemistry finally termin-ated this malpractice.

However, in a transformed fashion it continued ascellular therapy by injecting suspensions of fresh cellsof sheep embryos including testis cells, also for reju-venation and revitalization, well into the second halfof the twentieth century (Niehans 1952; 1960).

Meanwhile, science has progressed and, in the ageof cell biology, testicular transplantation continueswith the aim of inducing fertility, but now uses iso-lated germ cells (Brinster and Zimmermann 1994;Schlatt et al. 2002), and fertility has indeed beenrestored by this method in gamma-irradiated cocks(Trefil et al. 2006). Whether this may become amethod to treat male infertility, for example in


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Klinefelter patients (Wistuba 2010), remains to beseen, but at least it is pursued on a rational scientificbasis – as far as our present knowledge goes.

1.4 Twentieth-century scienceand medicine1.4.1 The rise of steroid biochemistryBerthold’s unique discovery was superseded byorganotherapy, but it was not permanently forgotten:Moritz Nussbaum (1850–1915), professor of anatomyin Bonn, repeated Berthold’s experiments and con-firmed the results in frogs (Nussbaum 1909), as didEugen Steinach in rats (Steinach 1910). Finally,A. Pézard confirmed Berthold’s original results incocks (Pézard 1911), and the search for the activeandrogenic substance in the testes began.

Fromobservation of the cock’s combgrowing underthe influence of transplanted testes, Moore et al. (1929)established the standardized capon comb’s test, meas-uring androgenic activity in square centimeters of combsurface. This first bioassay facilitated determination ofandrogenic activity in body products as well as in chem-ical solutions. S. Loewe and H. E. Voss (1930) used thebiological effects of androgens on the accessory sexorgans and developed the “cytological regenerationtest,” which was based on regrowth of the seminalvesicle epithelium under androgenic substances(Loewe–Voss test). The then still hypothetical malehormone was called “androkinin.”

Simultaneously, steroid biochemistry emerged andthe great breakthroughs were the discovery of the ringstructure of steroids and bile acids at the NationalInstitute of Medical Research in London (Rosenheimand King 1932) and at the Bavarian Academy of Sci-ences in Munich (Wieland and Dane 1932). A heateddiscussion started about whether there were three orfour rings in the steroid structure and, if four rings,whether the fourth had five or six carbon atoms. Underthe sponsorship of the Health Organization of theLeague of Nations (the predecessor of the WorldHealth Organization, WHO), famous chemists includ-ing Edmund A. Doisy, Adolf Butenandt and GuyMar-rian assembled at University College London andreached the consensus that steroids had four rings,and the fourth ring had five carbon atoms (Butenandt1980). Shortly before, these eminent researchers,including Ernest Laqueur, had isolated pregnanedioland estrone from pregnant mare urine provided by

various drug companies cooperating with scientists inorder to replace the miscredited organotherapy and tobring proper hormone substitution to patients (seeTable 1.1) (Simmer 1982).

1.4.2 Testosterone is bornIn 1931 Butenandt isolated the androgenic steroid,androsterone (androstan-3a-ol-17-one), from urine,for which he required 15 000 liters provided by young

Table 1.1 Early isolation of reproductive steroids (for referencessee the text)

1928Pregnanediol

Guy Frederick MarrianDept. Physiology andBiochemistry,University CollegeLondon

Crystallinematerial frompregnantmare urineprovided byBRITISHDRUGHOUSES

1929 Estrone Edward Albert DoisyDept. BiologicalChemistry, St. Louis

1929 Estrone Adolf ButenandtChemistry Laboratory,University ofGottingen

Raw extractsand crystalsfrompregnantmare urineprovided bySCHERING

1929 Estrone Ernst LaqueurPharmacotherapeuticLaboratory,Amsterdam

Benzeneextracts frompregnantmare urineprovided byORGANON

1931Androsterone

Adolf ButenandtChemistry Laboratory,University ofGottingen

Extractedfrom 15 000liters of urineprovided bythe PrussianPoliceAcademy inBerlin andprocessed bySCHERING

1935Testosterone

Ernst LaqueurPharmacotherapeuticLaboratory,Amsterdam

Isolated frombull testesProvided byORGANON


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policemen from Berlin, which was then processedby Schering to obtain 15 mg of this first androgen(Butenandt 1931). In 1935 Ernst Laqueur (1866–1947)and his group in Amsterdam extracted and isolated 10mg testosterone (androsten-17a-ol-3-one) from 100 kgof bull testes, which they found more active thanandrosterone, and named it “testosterone” (Davidet al. 1935). In the same year Butenandt and Hanisch(1935) as well as Ruzicka and Wettstein (1935)published the chemical synthesis of testosterone. Thismarked the beginning of modern clinical pharmaco-logy and endocrinology of testosterone, and malereproductive physiology.

Soon after its synthesis testosterone became clin-ically available, first in the form of pellets (Deansleyand Parkes 1937; Parkes 1965) and then as injectableesters, that is, testosterone propionate, with a shorthalf-life. And, from the mid-1950s on, the longer-acting testosterone enanthate (Junkmann 1952;1957) appeared, which remained the major testoster-one preparation for half a century. Also in 1935,17a-methyltestosterone was synthesized and its oraleffectiveness was demonstrated (Ruzicka et al. 1935).However, due to its 17a-structure it turned out to beliver toxic (Werner et al.1950; Nieschlag 1981), a factwhich gave testosterone in general a bad name amongphysicians, as this toxicity was also suspected fortestosterone without reason; eventually in the 1980sthis androgen became obsolete for clinical use inEurope. In the late 1970s the orally effective testoster-one undecanoate, absorbed from the gut via thelymph to avoid the first-pass effect in the liver, wasadded to the spectrum of testosterone preparationsused clinically (Coert et al. 1975; Nieschlag et al.1975) (see also Chapter 15).

In the 1950s and 1960s the pharmaceutical indus-try became more interested in new androgens than intestosterone itself, and concentrated its androgenresearch on the chemical modification of steroid mol-ecules in order to disentangle the various effects oftestosterone and produce predominantly erythropoie-tic or anabolic steroids (Kopera 1985). In 1956 con-temporary textbooks on androgens had alreadydescribed 256 androgenic steroids (Dorfman andShipley 1956), and by 1976 the number had increasedto more than 1000 (Kochakian 1976).

However, it proved impossible to produce andro-gens with only one effect out of the spectrum of testos-terone activities; at best, one of these effects could beemphasized, but the other effects remained. The

steroid with pure anabolic effects on muscles or bonesto treat cachexia, osteoporosis or small stature, or pureerythropoietic effect for the treatment of anemia with-out androgenization could not be found. Nevertheless,anabolic and similar steroids were clinically used, butdisappeared again in the wake of evidence-basedmedi-cine (Kopera 1985). However, they continued theirexistence for illegal use and abuse for doping in sportsand bodybuilding (see Chapters 24 and 25). Regret-tably, at that time the pharmaceutical industry neg-lected the chance to develop testosterone preparationsbetter suited for the substitution of hypogonadalpatients than the existing testosterone esters. Itremains to be seen whether the current search forselective androgen receptor modulators (SARMs) willtake a more rewarding course than did anabolic ster-oids (see Chapter 21).

From the 1970s the newly developed testosteroneimmunoassays (see Chapter 4) made serial testoster-one determinations in blood possible and, whenapplied to pharmacokinetic studies, it turned out thatall available testosterone preparations resulted inunphysiologically high or low serum levels which wereundesirable in substitution therapy. Clinicians assem-bled at a workshop on androgen therapy sponsored bythe WHO, and US National Institutes of health (NIH)and Food and Drug Administration (FDA) in 1990came to the conclusion: “The consensus view was thatthe major goal of therapy is to replace testosteronelevels at as close to physiologic concentrations as ispossible” (World Health Organization 1992), anddemanded that new testosterone preparations bettersuited for clinical use be manufactured.

In the mid-1990s, transdermal testosteronepatches applied to the scrotal skin became the firsttransdermal testosterone preparation in clinical use(Bals-Pratsch et al. 1986). They had been invented byVirgil Place at ALZA in Palo Alto, a company special-izing in new forms of delivery of known drugs (Atkin-son et al. 1998). However, although clinical resultswith this preparation were excellent, and for the firsttime physiological serum levels could be achievedunder testosterone substitution, physicians werereluctant to prescribe a medication to be applied tothe scrotum and preferred a subsequently developednon-scrotal system (Meikle et al. 1992). This, how-ever, caused unpleasant skin reactions as it requiredan enhancer to drive testosterone through the skin.For this reason the advent of the first transdermaltestosterone gel was welcome. This gel became


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available in 2000 for the treatment of male hypo-gonadism, first in the USA and later also in othercountries (Wang et al. 2000). Finally in 2004the intramuscular testosterone undecanoate prepar-ation entered the market and soon achieved greatpopularity as a real testosterone depot preparation(see Chapter 15).

Testosterone undecanoate had originally beenused in oral capsules (see above), but had been turnedinto an injectable preparation by Chinese investiga-tors using tea seed oil as a vehicle (Wang et al. 1991).When the author came across it at an exhibitionaccompanying an andrology symposium in Beijingin 1993, samples were brought to Germany, injectedinto monkeys and showed a surprisingly long half-life. A long half-life was confirmed in volunteeringhypogonadal men who all showed serum levels in thenormal range (Behre et al. 1999). When finally acompany was interested in this fascinating prepar-ation, it was “Europeanized” by using castor oil asvehicle and was developed as Nebido® for clinical use(Nieschlag 2006).

1.4.3 Early descriptions of syndromesof hypogonadismIt may not have been a coincidence, but rather a signof heightened interest in the hypogonadism clinics,that at the same time as testosterone became avail-able for clinical use (i.e. when rational treatmentbecame possible), the major syndromes of primaryand secondary hypogonadism were first described:that is, the Klinefelter syndrome (Klinefelter et al.1942) and the Kallmann syndrome (Kallmann et al.1944). Pasqualini and Bur (1950) described the firstcase of the fertile-eunuch syndrome, characterized byall symptoms of lack of testosterone, but activespermatogenesis; Del Castillo et al. (1947) publishedthe first five cases suffering from Sertoli-cell-onlysyndrome. Also at that time the symptoms of theaging male were first described systematically, butunfortunately wrongly termed as “male climacteric”(Werner 1945), starting a controversial discussionthat continues until today (see Chapter 16).E. C. Reifenstein (1947) first described a syndromewith partial androgen insensitivity (PAIS) thatcarries his name to date, and J. M. Morris (1953)published the first cases of complete androgeninsensitivity (CAIS) as “testicular feminization inmale pseudo-hermaphroditism” – of course without

knowing anything about the androgen receptor orandrogen receptor mutations (see Chapter 3).

At the same time, Huggins also posted hiswarning about testosterone influencing prostatecarcinoma (Huggins and Hodges 1941), which ledto castration (euphemistically called “orchidectomy”)as the major treatment of prostate carcinoma,and prevailed until quite recently when androgendeprivation therapy (ADT) by gonadotropin-releasing hormone (GnRH) analogs or antiandrogenswas introduced instead or in addition to castration(maximal androgen blockade = MAB). Huggins’statement, “Cancer of the prostate is activatedby androgen injections” induced a general fear oftestosterone, especially among urologists, that pre-vented testosterone treatment in many patientswho might have needed it. Only recently it becameclear that neither endogenous serum testosteronelevels (Endogenous Hormones and Prostate CancerCollaborative Group 2008) nor testosterone treat-ment (Raynaud 2006) have an impact on prostatecarcinogenesis, and now testosterone treatmentunder careful supervision is even considered forpatients after radical prostatectomy suffering fromtestosterone deficiency (Morgenthaler 2007). How-ever, orchidectomy will continue in the foreseeablefuture to remain the major option for treatment ofprostate carcinoma (Damber and Aus 2008). Thus,castration continues to be recommended for thera-peutic purposes as it had already been promulgatedduring Greco-Roman times and the Middle Ages forthe treatment of leprosy, epilepsy, gout, priapism,excessive masturbation and insanity (Melicow1977), reflecting the knowledge or rather the lack ofknowledge of the respective period. There remainsthe hope that research will eventually result in morehumane and patient-friendly methods of treatmentas we have witnessed the transition from castrationto ADT for treating sexual offenders (Gooren 2011).

1.5 Key messages

� The importance of the testes for normal malefunction and reproduction has been known sinceantiquity.

� Correspondingly, castration has also beenpracticed since antiquity to produce obedientslaves, harem custodians, civil servantsand soldiers, as well as for punishment andrevenge.


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