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Spermatogonial stem cell preservation in boys with klinefelter syndrome: to bank or not to bank, that's the questionSpermatogonial stem cellpreservation in boys with Klinefeltersyndrome: to bank or not to bank,that's the question Inge Gies, M.D.,a Jean De Schepper, M.D., Ph.D.,a Ellen Goossens, Ph.D.,b Dorien Van Saen, M.Sc.,bGuido Pennings, Ph.D.,c and Herman Tournaye, M.D., Ph.D.b,d a Department of Pediatrics, UZ Brussel, Brussels; b Research Group Biology of the Testis, Department of Embryology andGenetics, Vrije Universiteit Brussel, Brussels; c Bioethics Institute Ghent, Ghent University, Ghent; and d Centre forReproductive Medicine, UZ Brussel, Brussels, Belgium Although early development of testis appears normal in boys with Klinefelter syndrome (KS), spermatogonial stem cell (SSC) depletionoccurs in midpuberty, leading to infertility. Therefore, freezing of semen samples or testicular tissue sampling could be offered to boyswith KS at onset of puberty. However, only in about half of patients with KS, adult or prepubertal, spermatozoa or SSCs can be observed,and to date, no clinical parameters are available to detect patients who might beneﬁt from these techniques. Furthermore, strategies forthe further use of the cryopreserved material are still under investigation. Retrieval of spermato-gonial cells in prepubertal boys with KS should therefore still be viewed as experimental andpatients and their parents must be counseled accordingly. (Fertil SterilÒ 2012;98:284–9.
Ó2012 by American Society for Reproductive Medicine.) Key Words: Klinefelter syndrome, fertility preservation, spermatogonial stem cells Discuss: You can discuss this article with its authors and with other ASRM members at * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
Klinefeltersyndrome(KS)ischar- adiagnosispostnatallyandlessthan sociated with increasing FSH and were considered sterile, the ﬁnding of fo- a result of Sertoli cell dysfunction, vir- late adolescence or early adulthood.
recovery is testicular histopathology .
Received March 26, 2012; revised April 11, 2012; accepted April 16, 2012; published online May 17, with the onset of puberty, freezing of se- I.G. has nothing to disclose. J.D.S. has nothing to disclose. E.G. has nothing to disclose. D.V.S. has noth- ing to disclose. G.P. has nothing to disclose. H.T. has nothing to disclose.
Reprint requests: Inge Gies, M.D., Department of Pediatrics, UZ Brussel, Laarbeeklaan 101, 1090 Brus- puberty has been proposed, this beforeinitiating Fertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282/$36.00 Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
doi: might offer an even greater chance of retrieving gametogenic germ cells in the mature testis the proper X chromosome cells than in adulthood However, only limited data dose is crucial. Hence, molecular mechanisms induced by an exist on this approach and several unresolved questions still altered dose of X-encoded genes in testicular cells may, dur- ing puberty, initiate the degeneration process in the testes of knowledge of early germ cell retrieval in boys with KS together with its beneﬁts and pitfalls.
The androgen receptor (AR) gene on the X chromosome may play a particular role in differences in the KS phenotype.
The AR gene contains a polymorphic stretch of CAG repeats in exon 1. The length of this stretch is inversely related to recep- The development of the XXY mice in 1991 provided a tool to tor activity and inﬂuences physiological responses to an- investigate spermatogenesis in greater detail In these an- drogens. No data exist on the role of AR in germ cell numbers.
imal models, it was observed that normal numbers of primor-dial germ cells migrated to the genital ridges in the XXYembryo, and that impairment of the mitotic proliferation became evident only after the differentiation of the testis Nowadays, semen banking before any gonadotoxic treatment in adults and adolescents is considered as a valuable preven- The germ cell loss in XXY mice seems to start at a time tive measure in combination with techniques of assisted re- when germ cells in normal mice reinitiate mitosis and before production. Recommendations are made to universally bank the onset of germ cell meiosis. During this period, spermatogo- sperm for all males at Tanner stage III and above with newly nia are required to migrate from the central location to reach diagnosed malignancies, regardless of the planned treatment the periphery of the seminiferous cord to initiate proliferation.
Cryopreservation of human sperm has been reported for At this new location, spermatogonia are exposed to extracel- more than 25 years, and this without apparent loss of capacity lular matrix factors from the basal lamina and are thought to mature into the ﬁrst generation of type A spermatogonia. Any For boys unable to produce a sample by masturbation, al- germ cells that fail to move away from the laminal region of ternative procedures to collect sperm cells can be used, such as the seminiferous cord eventually degenerate. In a study by penile vibro- or electrostimulation and TESE .
Lue et al. it was shown that most of the degenerated When no sperm cells can be detected, testicular tissue germ cells were located near the central region of the seminif- cryopreservation may be offered for eventual restoration of erous cord, suggesting a defect in spermatogonial migration spermatogenesis from spermatogonial stem cells (SSCs) after during the postnatal period in XXY mice. It is not known completion of cancer treatment. One of the difﬁculties is to whether the defect in the XXY testis is intrinsic to germ cells store enough spermatogonial stem cells to restore fertility.
or whether it is due to the inability of the Sertoli cells to sup- Moreover, contaminating cancer cells must be detected and port normal germ cell development in XXY testis.
removed from testicular biopsy samples. After chemo- or ra- In humans, some reports suggest that the degeneration of diotherapy, the frozen-thawed SSCs could be reintroduced in germ cells already starts early in infancy, leading to a signiﬁ- the patient's own testis by SSC transplantation.
cantly reduced number of germ cells even before puberty The reduced number of germ cells has been observed in testicular biopsies on fetuses aborted at midtrimester Coerdt et al. observed only half of the number of spermatogonia in fetuses with KS at 19–22 weeks' gestation Sperm has been found in approximately 8% of ejaculated se- compared with normal XY fetuses. However, two other men samples of nonmosaic adult Klinefelter patients .
authors have reported normal testicular histology in 47,XXY However, Aksglaede et al. showed the absence of sperm fetuses aborted at 17 and 20 weeks .
in the ejaculate of 13 nonmosaic men with KS younger than As seen in the mouse model, also in boys with KS, germ cell differentiation seems to be arrested at the spermatogo- Several authors demonstrated spermatogenic foci in the nium or primary spermatocyte stage. At the onset of puberty, testis of many of the patients with KS Foresta et al.
spermatogonia go into apoptosis instead of entering meiosis performed FISH on testicular tissue of 10 nonmosaic men with KS and found residual spermatogenesis in 2 patients, mature Sertoli cells are incapable of transforming into the and Sertoli cells were cytologically identiﬁed in all 10.
Several authors tried to retrieve spermatozoa by TESE at an Genetic features of the X chromosome appear to play early stage for cryopreservation and future utilization .
a role in modulating KS phenotypes. The supernumerary X om et al. found that only 50% of 14 boys with KS chromosome is inherited paternally in 40%–60% and mater- aged 10–14 years who had undergone biopsy had germ cells in their testis, indicating severely impaired fertility potential Skewed X chromosome inactivation, frequently observed even in the peripubertal period. All of the seven boys in in females, and deﬁned as greater than 80% preferential inac- whom stem cells were found were younger than 12 years and tivation of one of the two X chromosomes, also occurs in KS had prepubertal-sized testicular volumes and normal serum in- X-reactivation occurs during germ cell development in hibin B and FSH concentrations. The same authors found that the XXY mouse, and it is assumed that for the survival of the number of adult dark spermatogonia was markedly reduced in adolescents with KS, again indicating a severely im- it is not clear whether these two populations showing either paired fertility potential even before puberty.
spermatogonia in adolescence or spermatozoa in adulthood uller et al. could not ﬁnd any germ cells in their testes represent the same or a different subpopulation in 11 boys with KS beyond the age of 2 years. However, in this of patients with KS. However, given the limited number of study, all boys had cryptorchidism. Damani et al. also re- adolescents with KS investigated to date and the lack of ported spermatogonial stem cells in the testicular tissue of reliable longitudinal histologic data, we cannot exclude a 15-year-old boy with KS with testicular volume of 10 mL, the possibility that in some of these adolescents the and presenting with elevated FSH concentration. Aksglaede hyalinization process might progress very rapidly, making it et al. described the loss of germ cells from the age of 10 unlikely to ﬁnd residual spermatozoa when sampling is years in an observational retrospective study with 29 testicu- performed in adulthood. Certainly, cryopreservation of lar cell biopsies from variable ages.
semen samples that contain even minuscule numbers of Our own data show that spermatogonia were observed in spermatozoa could be offered to all adolescents with KS who 18% of adult men with KS in whom no testicular spermatozoa are interested in their future fertility.
were retrieved, whereas spermatogenesis up to the spermato-cyte level was observed in 14% of them Furthermore, webiopsied seven adolescent patients with KS, aged 10–16 years, and observed spermatogonia in approximately half of them Our data show that spermaturia was absent in 7 boys with KS but failed to ﬁnd any meiotic germ cells in these boys. In older than 12 years . Also Ratcliffe et al. could not none of them were we able to retrieve spermatozoa .
ﬁnd spermatozoa in the morning urine in a group of 12 puber-tal boys with KS older than 16 years. Conventional semencryopreservation is thus a nonissue. Banking testicular germ cell, however, remains a possibility.
Spermatogonial stem cells can be cryopreserved as a cell that, for an optimal preservation of SSCs, testicular tissue suspension or as intact tissue. Cell suspensions are regarded preservation should preferentially be proposed before as easier to cryopreserve but preparation of cell suspensions re- hyalinization occurs. To offer an optimal preservation of quires mechanical or enzymatic digestion of tissue, which can SSCs, an early detection of the syndrome, that is, before compromise cell survival For human testicular cell suspen- sions, a post-thaw viability of up to 60% was achieved, regard- Serum inhibin B levels during prepuberty and early pu- less of the cryoprotective agent. Alternatively, cryopreservation berty are normal This suggests that during early of testicular tissue pieces can be used and employed in testicular puberty, serum inhibin B levels in boys with KS reﬂect the autografting, or enzymatically dispersed. Cryopreservation of integrity or number of Sertoli cells or both. However, in the testicular tissue maintains cell-to-cell contacts between germ cells and thus preserves the stem cell niche necessary for their low testosterone levels were inconsistent with the presence survival and subsequent maturation. Cryoprotection with eth- ylene glycol and dimethyl sulfoxide using slow-programmed rise during prepuberty and early puberty in boys with KS freezing have been applied for cryopreservation of testicular and decline thereafter, could not serve as an indicator of tissue Dimethyl sulfoxide, rather than ethylene spermatogenetic activity in boys with KS . Insulin-like glycol, propanediol, or glycerol, better preserves structures factor 3 (INSL3) levels, as a marker of Leydig cell function, within human testicular tissue and better maintains were found to be normal in both infants with KS and early tissue capacity to initiate spermatogenesis in nonhuman pubertal boys with KS and decrease to very low levels in primate tissue . Furthermore, slow-programmed freezing adult men with KS . No clear correlation with germ cell seems to better protect spermatogonial morphology. Further modiﬁcation of this protocol with addition of sucrose has Testicular tissue preservation should thus preferentially be shown to abolish the spermatogonial and Sertoli cell loss during proposed before any decline in serum inhibin B is observed freezing–thawing, and spermatogonia have been able to prolif- whenever optimal preservation of spermatogonial stem cells erate after orthotopic xenografting .
is anticipated. On the other hand, it is unknown whether in ad- An important point for cryopreservation of testicular ma- olescents with KS in whom spermatogonia are detected, focal terial is the removal of sufﬁcient, but not extensive, amount spermatogenesis might persist until adulthood. It is tempting of testicular tissue. In prepubertal testes, the absence of differ- to speculate that the potential of maintaining spermatogonial entiating germ cells creates a relative enrichment of sper- stem cells and focal spermatogenesis is already programmed in matogonial stem cells compared with adult testes. Pediatric utero. This would explain the ﬁnding of spermatogonial stem patients may therefore require a smaller amount of tissue cells in half of patients with KS at different ages. In fetuses for fertility preservation than adults. There are no human or with KS at 19–22 weeks of gestation, spermatogonia were nonhuman primate studies revealing how many spermato- found to be reduced to approximately half of the number ob- genic stem cells can be retrieved from the prepubertal testis.
served in normal XY fetuses It is striking that although According to morphological studies, it is estimated that one spermatogonia are found in half of the adolescent patients in testis of a 10-year-old prepubertal healthy boy contains ap- whom a biopsy was performed, successful recovery of sperma- proximately 83 Â 106 germ cells however, there are no tozoa by TESE in adults is also around 50% At present, data on patients with KS. It is likely that spermatogonial stem cell transplantation is not clinically applicable without material. The experimental nature of the whole procedure, a method to expand spermatogenic stem cells or to increase combined with the need for surgical intervention on minors, their colonization capacity. It was estimated that a 1,300- strongly urges a cautious approach. The absence of a proof fold expansion of SSCs would be necessary to entirely colo- of principle is important at this point but one success would nize the adult testis. Recently, a culture system was developed not change the situation drastically. Present research should for prepubertal or adult human spermatogonia enabling this focus on the parameters that could help identify which boys with KS would most likely beneﬁt from testicular tissuefreezing.
A recent study of Maiburg et al. showed that 70% of men with KS and 74% of their partners would opt for TESE- The possible future use for infertility treatments using cryo- ICSI in order to father a child. Ninety-ﬁve percent of the par- preserved testicular samples containing spermatogonia but ents estimated this treatment a valuable option for their sons.
no mature germ cells would require in vitro maturation of In addition, Vernaeve et al. reported that 69% of the KS spermatogonia into mature spermatozoa or at least into couples, after counseling by a psychologist and gynecologist, late/elongated spermatids. Human testicular tissue can be wanted to try new techniques like ICSI, TESE, or preimplanta- cultured for at least up to 3 weeks without essential loss of tion genetic diagnosis. So, assuming that the technical prob- spermatogonia Meiosis and spermatogenesis also seem lems will be solved, there is a willingness to use assisted to resume under culture conditions, yielding normal sperma- reproduction to realize a child wish. However, the utilization rate of frozen tissue will also be determined by alternatives Several potential strategies are currently under investiga- and need: in approximately 55% of men spermatozoa can tion for the further use of cryopreserved spermatogonial stem be recovered at adult age, only about 50 percent of men with KS had a partner at the age of 40 .
Germ cells could be transplanted using a cryopreserved The general position on whether or not to offer storage of single-cell suspension infused back into the seminiferous tu- testicular tissue to all boys with KS will depend on arguments bules of the infertile patient. However, because KS testes are such as the importance of genetic parenthood and the optimism characterized by extensive ﬁbrosis and hyalinization of the regarding the future evolution of science and medicine .
seminiferous tubules, the ultimate use of the frozen tissue These beliefs are in the present context of uncertainty more im- may be different. Yet, Lue et al. demonstrated that the portant to decide whether the best interests of the boy with KS transplantation of euploid germ cells into germ cell- are served by an intervention than purely technical aspects.
deﬁcient XXY mice could restore spermatogenesis, indicatingthat the somatic niche of the XXY testis is capable of support-ing germ cell development in the mouse.
As an alternative, spermatozoa could be generated from In about half of patients with KS, adult or prepubertal, respec- spermatogonial stem cells via in vitro differentiation. A tively, spermatozoa or spermatogonial stem cells can be ob- three-dimensional soft agar culture system has been devel- served and eventually cryopreserved for future fertility.
oped for mouse SSCs that allows the in vitro differentiation However, to date, it is not clear whether in the remaining pa- of spermatogonial stem cells into postmeiotic spermatozoa tients earlier retrieval for spermatogonial stem cells could im- Future studies are required to determine whether sperm prove this retrieval rate, because uterine programming of the generated in vitro maintains DNA integrity or whether no epi- number of germ cells might come into play, leading to only genetic changes occur, which might have long-term implica- half of patients with KS having germ cells left after birth. Fur- tions for the health of any resulting offspring or even in thermore, no clinical parameters are available to detect pa- tients who might beneﬁt from testicular tissue banking. To be able to perform long-term studies on younger patients tosolve this question, earlier diagnosis of KS is necessary.
To date, patients must be counseled that fertility preser- The primary question in the ethical evaluation is whether col- vation is an emerging ﬁeld, but with many unanswered ques- lecting, freezing, and possible later usage of the tissue serves tions remaining. Retrieval of spermatogonial cells in the best interests of the child. This means that the costs (e.g., prepubertal boys with KS should be viewed as experimental testicular biopsy, storage, and ﬁnancial costs) should be offset and patients and their parents must be counseled accordingly.
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