Journal of Reproductive lmmunology, 18 (1990) 1--8


Elsevier Scientific Publishers Ireland Ltd.


The testis and tissue transplantation: historical aspects B r i a n P . Setchell Department of Animal Sciences, Waite Agricultural Research Institute, University of Adelaide, Glen Osmond, South Australia 5064 (Australia)

Summary Transplantation experiments involving the testis have been performed since the days of John Hunter, who transplanted a testis into the belly of a hen. The first person to use the testis as a site of transplantation appears to have been Sand, who found in 1919 that an ovary transplanted into the substance of the testis developed follicles. By 1970, there was considerable evidence that the testis under some circumstances was a relatively favorable site for graft survival. However, much of the evidence was equivocal, and the immunological privilege was by no means complete. Key words:

testis; transplantation; history.

Transplantation experiments involving the testis have been of two types, those in which the testis was the tissue to be transplanted and those in which the testis was the recipient site. The earliest experiments were of the former type and the first recorded are those by John Hunter, who transplanted the testis of a cock into the belly o f a hen (see Qvist, 1981). The testis adhered to the intestine or the peritoneum, but appeared to have no effect on the " n a t u ral disposition" o f the recipient. The specimens are still in the Hunterian Museum in L o n d o n and photographs of them have now been published; histological examination o f sections conducted at the beginning of this century showed that the testes have " a perfectly normal structure" (see J6rgensen, 1971). Hunter himself did not publish a detailed description o f the experiments and we must depend on the notes taken at his lectures and the recollections of visitors. Hunter's experiments were soon repeated by Michaelis (1785), who also transplanted a testis into a cock's comb. 0165-0378/90/$03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland

The next important series of transplantation experiments were those carried out by Berthold, and reported in two almost identical papers in 1849 (see Setchell, 1984). Berthold castrated six roosters: in two, one testis was returned to their own abdominal cavity, in two others, one testis was transferred to the abdominal cavity of the other bird, and two were left as controls. Male sex characteristics were retained only in those birds with a grafted testis, and Berthold suggested that these effects were produced by "the productive function of the testes, i.e. by their action on the blood stream, and then by the corresponding reaction of the blood upon the entire organism" (from translation by Quiring, 1944). These experiments are widely believed to be the beginning of modern endocrinology (see J6rgensen, 1971; Setchell, 1984), but it is curious that so little attention was paid to them at the time. Wagner, probably the greatest physiologist of his day, and a colleague of Berthold's at G6ttingen, was unable to repeat the results (Wagner, 1851), and it was only at the end of the nineteenth century that successful transplants were again reported (Lode, 1895; Hanau, 1897; Foges, 1898), by which time the concept of internal secretion was firmly established and the endocrinological significance of the experiments was accepted. Even in 1930, Greenwood and Blyth reported only 5 successes out of 24 grafts of rooster testes into hens. In the earlier studies, transplantation of the testes of mammals appeared to be more difficult and it was only with the work of Cevelotto (1909), Steinach (1910) and Sand (1919) that successful results were reported. Even in the successful grafts, in many instances the seminiferous tubules atrophied and the interstitial tissue appeared to hypertrophy, to produce the so-called "puberty-gland". The series of experiments described by Moore (1926) explained many of the failures, especially of the tubular tissue, by the effects of temperatures higher than those normally found in the scrotum, and complete spermatogenesis was achieved if the grafts were placed in the peritoneal cavity of the scrotum or, as Richter and Wislocki (1928) did, under the scrotal skin. Deanesly (1954) showed that testes of new-born rats, even after they had been frozen to - 7 9 ° C , secreted androgens and produced spermatozoa when grafted under the scrotal skin of castrated adult recipients. Leckband (1964) found that allogeneic grafts under the scrotal skin survived as well as syngeneic grafts if the recipient mice were made tolerant by the injection of allogeneic spleen cells at birth, and rejection of these grafts could be induced by the injection of spleen cells sensitized to the appropriate antigens. Subsequently, Turner (1938) and Dameron (1950, 1951a,b) showed that complete spermatogenesis could also be achieved in testicular grafts placed in the anterior chamber of the eye, which presumably also was cooler than body temperature. Williams (1950) found that some spermatogenic activity persisted in tubular grafts placed in transparent chambers in rabbits' ears, whereas interstitial tissue grafted in the same way

produced some interesting changes in the ingrowing blood vessels (Williams, 1949). Pfeiffer (1935) used transplanted testes of new-born rats into littermate females to demonstrate a masculinising effect of the testis on the pituitary. Others (Burrill and Greene, 1940; Krichevsky et al., 1943) used intrasplenic grafts of testes to demonstrate that testicular androgens were inactivated by the liver, even when the excessive gonadotrophin secretion by the castrated host produced tumours of the testicular grafts (Biskind and Biskind, 1945; Li et al., 1947). Grafts of fetal testes and ovaries under the kidney capsule, subcutaneously or onto the omentum were used to study factors influencing differentiation of the gonad (Buyse, 1935; Moore and Price, 1942; Holyoke, 1949; Macintyre, 1956; Macintyre et al., 1960). In some instances, the grafts grew better in castrated hosts, presumably because of the increased gonadotrophin secretion (see Moore and Price, 1942); in other studies there was no effect. Testes from embryos or new-born donors survived better than similar sized fragments from adult animals (Larkin, 1960). An interesting series of trials were conducted by Serge Voronoff from 1919 onwards, based on the earlier claims by Brown-Sequard for the rejuvenating effects of testis extracts. Voronoff began by transplanting fragments of testes of young rams to the scarified tunica albuginea of the testes of old animals, and claimed to have restored the virility and general wellbeing of the recipients, as well as increasing their wool production. He went on to propose similar grafts in humans, but testis grafts had already been performed in the U.S.A. by Lespinasse (1913) and Lydston (1914); the latter even performed a graft on himself. A testis graft from an executed murderer into a 60 year-old prison inmate was reported in 1920 by Stanley. Thorek (1924) also reported the results of transplants of human testes to other humans and to monkeys and of monkey testes to other monkeys. Voronoff soon extended his own work to humans, using tissue from monkeys, and considerable notoriety was gained by a quack " D r " Brinkley of Kansas, who transplanted goat testes into his patients. Steinach in Vienna also joined in the rejuvenation business, using guinea pig testes for his grafts. Voronoff was assisted in his attempts to make his procedures acceptable by Retterer, who published a number of reports of the histology of grafted testes, recovered both from experimental animals and patients. Many other surgeons began to perform testis grafts, and claimed sensational results, although in all instances the observations were completely uncontrolled. Voronoff's work on testis grafting in sheep in Algeria was investigated by a group of scientists from Great Britain, including F.H.A. Marshall of "Marshall's Physiology of Reproduction", F.A.E. Crew, who was one of the first to suggest that temperature had a deleterious effect on the testis, and Arthur Walton, who subsequently made such important contributions in the

techniques of artificial insemination. They could find no evidence to support Voronoff's claims (Marshall et al., 1928), and further criticism of the experiments was made by Velu (1931) in France and Gunn and Seddon (1931) in Australia. Rejuvenation by testis grafting became less fashionable, and the dangers of transmission of diseases from the monkeys to the patients became apparent (see Hamilton (1986) for a detailed description of Voronoff's career; see also Krohn (1955) for an extensive bibliography). Transplants from mice to rats and vice versa were uniformly unsuccessful (Crisler, 1929; Browman, 1937). The first person to use the testis as a site of transplantation appears to have been Sand (1919, 1923), who found that an ovary transplanted into the substance of the testis developed follicles. In 1935, Gardner and Hill reported (see also Hill and Gardner, 1936) that pituitary grafts persisted in the testes of mice, and stated that " m a n y investigators have found the testis to be a favourable site for ovarian transplants", without giving any references. May (1960) implanted a pituitary into the testis of an hypophysectomized mouse and showed that testicular function was restored. Gonet and Renold (1965) reported that fetal pancreas grafted into the testes of diabetic rats survived in about 20°70 of recipients; the grafts were generally larger than those in the eye and appreciable amounts of insulin could be detected in them, with a variable reduction in glycosuria. Hultquist and Thorell (1964) also reported that islet tissue from rats and guinea pigs could be successfully grafted into the testis if the acinar tissue of the pancreas was eliminated by ligation of the pancreatic duct. Greene (1940, 1942, 1949) used the testis as one site for transplanting tumours in several species, although he obtained success in only a small proportion of animals. In his experiments, the testis appeared to be a no better site than subcutaneous tissue, while the anterior chamber of the eye was clearly superior. Likewise, Medawar and Russell (1958) transplanted adrenals to the testes of mice, as well as the anterior chamber of the eye, the brain and muscle. The proportions of the grafts surviving after 14 days were 4/12 for those placed in the testis, 7/10 for those in the eye, 4/22 for those in brain and 2/14 for those in muscle; testis is not significantly better than muscle or worse than eye, although eye is significantly better than muscle (by X:). On the other hand, Aron, Marescaux and Petrovic (1957) reported that grafts of pituitary, thyroid and ovary persisted more often in the testis than in other sites. The grafted thyroids were able to accumulate radioactive iodine (Aron et al., 1955). Subsequently, Turner and Asekawa (1963), Luxembourger and Aron (1966) and Aron and Luxembourger (1968) showed that testes from new-born rats attained complete spermatogenesis when transplanted into the testes of adults, at a rate similar or slightly slower than those in situ; most of the delay appeared to occur immediately after the operation. In contrast to these observations, Arrau et al. (1988) found that growth and differentiation of fetal hamster gonads were

inhibited following transplantation to the testes of adults. Pilsworth (1979) found that testes of new-born rats grafted into the testes of adults for 35 days had significantly fewer tubular cross-sections in meiotic prophase than control 35 day-old animals, and while dividing the testis into two halves significantly increased the proportion of tubule cross-sections in meiotic prophase, the presence or absence of the rete had no influence. On the other hand, when the grafts were placed subcutaneously under the scrotal skin there was a much greater lymphocytic infiltration and the presence of a rete appeared to be necessary for meiosis to proceed. Bressler and Ross (1972) and Bressler (1976) used testes of new-born mice transplanted into adult hosts (intact, hypophysectomized or hypophysectomised - - testosterone treated) to show that maturation of both the myoid cells and the Sertoli cells was under hormonal control. Transplantation of fragments of placenta to the testis of prepubertal rats was used to demonstrate that the placenta in this species did not produce gonadotrophins, by showing that after 5 days the testis was not altered in the vicinity of the graft (Canivenc, 1956). Intratesticular grafts of ovaries and vaginae were used by Takewaki (1956, 1957, 1958, 1959) to study the secretion of oestrogens by the Sertoli cells and the antagonism between androgens and oestrogens on vaginal cornification; most of the grafts persisted for between 1 and 2 months before hormone treatment was begun, but subcutaneous grafts were apparently just as successful as those in the testes. Kirby (1963, 1971) and Billington (1965) transplanted blastocysts and ectoplacental cones to various sites, including the testis. Almost 100% of the ectoplacental cones developed in all sites used, but the proportion of blastocysts that developed depended on the transplantation site: testis 80--90°7o; kidney 80°/0; brain 50--60°/0; spleen and anterior chamber of the eye 25-35%; other sites less than 25%. Furthermore, Kirby made the intriguing observation that about 40% of the blastocysts transplanted to a scrotal testis developed embryonic shield derivatives, compared with about 30% in the kidney but only 4% if the testis was cryptorchid. It was also found that the testis was the only site where the transplanted trophoblast produced cytolytic destruction of the host tissue (Billington, 1965; Bland and Donovan, 1965). In summary, it was generally accepted by 1970 (see e.g., Russell and Monaco, 1964) that the testis under some circumstances was a relatively favorable site for graft survival. However, it would now appear that much of the evidence was equivocal, and the immunological privilege was by no means complete. References Aron, M. and Luxembourger, M.-M. (1968) Facteurs de l'6volution spermatog6n6tique et de l'6volution de la glande interstitielle avant la maturit6 sexuelle. Etude chez le rat par I'homotransplantation du testicule n6o-natal dans le testicule de I'animal mur. Arch. Anat. Histol. Embryol. 51,41--52.

Aron, M., Gros, C., Petrovic, A. and Gegauff, C. (1955) Particularit6s de la fixation d'I TM par les greffons thyroidiens intra-testiculaires chez le Cobaye. CR Soc. Biol. 149,407--409. Aron, M., Marescaux, J. and Petrovic, A. (1957) Greffes homoplastiques chez le mammiferes. Colloq. Int. CNRS. 78, 25--33. Arrau, J., Bustos-Obregon, E. and Cabello, R. (1988) Inhibition of growth and differentiation of fetal hamster gonads grafted into the adult testis. Int. J. Androl. 11,327--338. Billington, W.D. (1965) The invasiveness of transplanted mouse trophoblast and the influence of immunological factors. J. Reprod. Fertil. 10, 343--352. Biskind, M.S. and Biskind, G.R. (1945) Tumor of rat testis produced by heterotransplantation of infantile testis to spleen of adult castrate. Proc. Soc. Exp. Biol Med 59, 4--8. 'Bland, K.P. and Don0van, B.T. (1965) Experimental ectopic implantation of eggs and early embryos in guinea pigs. J. Reprod. Fertil. 10, 189-- 196. Bressler, R.S. (1976). Dependence of Sertoli cell maturation on the pituitary gland in the mouse. Am. J. Anat. 147,447--456. Bressler, R.S. and Ross, M.H. (1972). Differentiation of peritubular myoid cells of the testis: Effects of intratcsticular implantation of new-born mouse testes into normal and hypophysectomized adults. Biol. Reprod. 6, 148--159. Browman, L.G. (1937) Testicular heterotransplantation in rats and mice. J. Exp. Zool. 75,283--311. Burrill, M.W. and Greene, R.R. (1940) The liver and endogenous androgens. Proc. Soc. Exp. Biol. Med. 44, 273--276. Buyse, A. (1935) The differentiation of transplanted mammalian gonad primordia. J. Exp. Zool. 70, t - 41. Canivenc, R. (1956) Le placenta de rat et son activit6 endocrine. Arch. Anat., Histol. Embryol. 39, 1-95. Cevelotto, G. (1909) Ober Verpfanzungen und Gefuerungen der Hoden, Frank. Zeitschr. Path. 3,331-337. Crisler, G. (1929) The heterogeneous testis transplant problem as applied to white rats and mice. Am. J. Physiol. 90, 623--630. Dameron, J.T. (1950) Homologous transplantation of fetal endocrine tissue to adult non-related host. Proc. Soc. Exp. Biol. Med. 73,343--345. Dameron, J.T. (1951a) The anterior chamber of the eye for investigative purposes. A site for transplantation of fetal endocrine tissues and cancer, and for the study of tissue reaction. Surgery 30, 787--799. Dameron, J.T. (195 lb) Homologous transplantation of endocrine tissues. Surg. Forum 1,570--578. Deanesly, R. (1954) Spermatogenesis and endocrine activity in grafts of frozen and thawed rat testis. J. Endocrinol. 11,201--206. Foges, A. (1898) Zfir Hodentransplantation bei H~ihnen. Centrlbl. Physiol. 12, 898--901. Gardner, W.U. and Hill, R.T. (1935) Persistence of pituitary grafts in the testis of the mouse. Proc. Soc. Exp. Biol. Med. 32, 1382--1384. Gonet, A.E. and Renold, A.E. (1965) Homografting of fetal rat pancreas. Diabetologia 1,91--96. Greene, H.S.N. (1940) Familial tumours in the rabbit. IV. The evolution of autonomy in the course of tumor development as indicated by transplantation experiments. J. Exp. Med. 71,305--324. Greene, H.S.N. (1942) Heterologous transplantation of a human fibrosarcoma. Cancer Res. 2,649--654. Greene, H.S.N. (1949) Heterologous transplantation of the Brown-Pearce tumour. Cancer Res. 9, 728-735. Greenwood, A.W. and Blyth, J.S.S. (1930) The results of testicular transplantation in Brown Leghorn hens. Proc. R. Soc. Lond. B. 106, 189--202. Gunn, R.M.C. and Seddon, H.R. (1931) Testicular grafts on rams. Aust. Vet. J. 6, 104--112 and 132-145. Hamilton, D. (1986)The monkey gland affair. Chatto and Windus, London. Hanau, A. (1897) Versuche fiber den Einfuss der Geschlechtsdriisen auf die secund~iren Sexualcharactere. Arch. Ges. Physiol. 65,516--617. Hill, R.T. and Gardner, W.U. (1936) Function of pituitary grafts in mice. Proc. Soc. Exp. Biol. Med. 34, 78--79. Holyoke, E.A. (1949) The differentiation of embryonic gonads transplanted to the adult omentum in the albino rat. Anat. Rec. 103,675--699.

Hultquist, G.T. and Thorell, J. (1964) A method for isolating islets of Langerhans by transplantation. Acta Soc. Med. Uppsal. 69, 291--304. J6rgensen, C.B. (1971) John Hunter, A.A. Berthold and origins of endocrinology. Acta Hist. Scient. Natural. Medic. 24, 1--54. Kirby, D.R.S. (1963) The development of mouse blastocysts transplanted to the scrotal and cryptorchid testis. J. Anat. 97, 119--130. Kirby, D.R.S. (1971) The transplantation of mouse eggs and trophoblast to extrauterine sites. In: Methods in Mammalian Embryology (Daniel, J .C., Freeman, W.H., eds.), pp. 146--156. San Fransisco. Krichevsky, B., Benjamin, J.A. and Slater, C. (1943) Inactivation of endogenous androgens by the liver in rabbits. Endocrinology 32,345--350. Krohn, P.L. (1955) Bibliography of testis transplantation. Transplant Bull. 2, i 10--116. Larkin, J.H. (1960) Differentiation of first- and second-set grafts of embryonic, neonatal and adult testis implanted beneath the kidney capsule of adult rat hosts. Am. J. Anat. 106, 73--87. Leckband, E. (1964) Testicular homografts in tolerant mice. Transplantation 2, 522--533. Lespinasse, V.D. (1913)Transplantation of the testicle. ,I. Am. Meal. Assoc. 61, 1869. Li, M.H., Pfeiffer, C.A. and Gardner, W.U. (1947)imrasplenic transplantation of testes in castrated mice. Proc. Soc. Exp. Biol. Med. 64, 319--323. Lode, A. (1895) Zur Transplantation der Hoden bie H/ihnen. Wien. Klin. Wochenschr. 8, 345. Luxembourger, M.-M. and Aron, M. (1966) Etude, par l'homotransplantation de testicule n6o-natal de rat dans le testicule du rat mur, des facteurs de l'evolution spermatog6n6tique avant la maturit6 et des facteurs de l'involution de la lign6e s6minale darts le testicule priv6 de voies excr6trices. C.R. Soc. Biol. 160, 391~394. Lydston, G.F. (1914) Transplantation of a testicle from the dead to the living body: suggestiveness of results in their relation to the etiology and treatment of psoriasis, carcinoma etc. (A preliminary report). N.Y. Med. J. 100, 67. Maclntyre, M.N. (1956) Effect of the testis on ovarian differentiation in heterosexual embryonic rat gonad transplants. Anat. Rec. 124, 27--45. Maclntyre, M.N., Hunter, J.E. and Morgan, A.H. (1960) Spatial limits of activity of fetal gonadal inductors in the rat. Anat. Rec. 138, 137--147. Marshall, F.H.A., Crew, F.A.E., Walton, A. and Miller, W.C. (1928) Report on Dr. Voronoff's experiments on the improvement of livestock. H.M.S. Stationary Office, London. May, R.M. (1960) The dormant state in tissue transplantation as exemplified by subcapsular grafts of testicles from hypophysectomized mice. Ann. N.Y. Acad. Sci. 87,501--51 i. Medawar, P.B. and Russell, P.S. (1958) Adrenal homografts in mice, with special reference to immunological adrenalectomy. Immunology 1, 1--12. Michaelis, F. (1785) Ober die Regeneration der Nerven. Cassel. (quoted by J6rgensen, 1971). Moore, C.R. (1926) On the properties of the gonads as controllers of somatic and psysical characteristics. IX. Testis graft reactions in different environments (rat). Am. J. Anat. 37, 351--416. Moore, C.R. and Price, D. (1942) Differentiation of embryonic reproductive tissues of the rat after transplantation into post-natal hosts. J. Exp. Zool. 90, 229--265. Pfeiffer, C.A. (1935) Origin of functional differences between male and female hypophyses. Proc. Soc. Exp. Biol. Med. 32,603--605. Pilsworth, L.M.C. (1979) The roles of the blood-testis barrier and luminal fluids of the testis in meiosis. Ph.D. Dissertation, University of Cambridge. Quiring D.P. (1944) The transplantation of testes. Arnold Adolf Berthold. Bull. Hist. Med. 16, 399-401. Qvist, G. (1981) John Hunter 1728--1793. William Heinemann, London. Richter, C.P. and Wislocki, G.B. (1928) Activity studies on castrated male and female rats with testicular grafts, in correlation with histological studies of the grafts. Am. J. Physiol. 86, 651--660. Russell, P.S. and Monaco, A.P. (1964) The biology of tissue transplantation. Little, Brown and Company, Boston. Sand, K. (1919) Experiments on the internal secretion of the sexual glands, especially on experimental hermaphroditism. J. Physiol. 53,257--263. Sand, K. (1923) Experiments on the endocrinology of the sexual glands. Endocrinology 7,273--301.

Setchell, B.P. (1984) Male Reproduction. Benchmark Papers in Human Physiology, Volume 17 (Langley, L.L., series ed.), 401 pp. Van Nostrand Reinhold Company, New York. Stanley, L.L. (1920) Experiences in testicle transplantation. Cal. State J. Med. (San Fransisco) 18, 251-253. Steinach, E. (1910) Geschelchtstrieb und echtsekund~ire Geschelchtsmerkmale als folgender innersekretorischen Funktion der Keimdrtisen. Centrlbl. Physiol. 24, 551--566. Takewaki, K. (1956) Difference in response to injections of estrogen between intratesticular and subcutaneous vaginal transplants in male rats. J. Fac. Sci. Tokyo Uni. Section IV 7,641--653. Takewaki, K. (1957) Effect of cryptorchidism and unilateral castration on response of vaginal transplants in male rats. J. Fac. Sci. Tokyo Uni. Section IV 8, 191--197. Takewaki, K. (1958) Estrogenic effect of ovarian grafts on intratesticular and subcutaneous vaginal transplants in normal and cryptorchid male rats. J. Fac. Sci. Tokyo Uni. Section IV 8,337--345. Takewaki, K. (1959) Difference in response to oestrogen supplied by ovarian grafts and that administered by injection between intratesticular and subcutaneous vaginal transplants in male rats. Arch. Anat. Microsc. Morphol. Exp. 48,275--284. Thorek, M. (1924) Experimental investigations of the role of the Leydig, seminiferous and Sertoli cells and effects of testicular transplantation. Endocrinology 8, 61--90. Turner, C.D. (1938) Intra-ocular homotransplantation of prepuberal testes in the rat. Am. J. Anat. 63, 101--159. Turner, C.D. and Asakawa, H. (1963) Complete spermatogenesis in intratesticular homotransplants of fetal and neonatal testes in the rat. Proc. Soc. Exp. Biol. Med. 112, 132--135. Velu, H (1931) Etat actuel de nos connaissances sur la greffe testicularire. La Presse Medicale 39, 1496-1498. Wagner, R. (1851) Mittheilung einer einfachen Methode zu Versuchen tiber die Ver/inderungen thierischer Gewebe in morphologischer und chemischer Beziehung. Nachrichten Kg. Ges. Wissensch. G6ttingen 1851, 97--109. (quoted by JOrgensen, 1971). Williams, R.G. (1949) Some responses of living blood vessels and connective tissue to testicular grafts in rabbits. Anat. Rec. 104, 147--161. Williams, R.G. (1950) Studies of living interstitial cells and pieces of seminiferous tubules in autogenous grafts of testis. Am. J. Anat. 86, 343--367.

The testis and tissue transplantation: historical aspects.

Transplantation experiments involving the testis have been performed since the days of John Hunter, who transplanted a testis into the belly of a hen...
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