The natural history of endocrine function and spermatogenesis in Klinefelter syndrome: what the data show
2012; Elsevier BV; Volume: 98; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2012.06.024
ISSN1556-5653
Autores Tópico(s)Sexual Differentiation and Disorders
ResumoOnce thought to be a chromosomal aberration associated with absolute sterility, Klinefelter syndrome may now be potentially treatable by testicular sperm retrieval coupled with intracytoplasmic sperm injection. With these therapeutic advances, azoospermic 47,XXY men now may have an opportunity for biological paternity. However, our knowledge of the basic mechanisms underlying germ cell loss and Leydig cell compromise is lagging, and is just now beginning to evolve and provide answers to some of the field's most vexing questions: how to maximize and preserve fertility in Klinefelter males many years or even decades before they wish to actively pursue fatherhood. This article reviews the development of the androgenic and spermatogenic compartments of the Klinefelter testis through puberty, and recommends that it is only with a clear understanding of the basic facts that a rational, considered approach to fertility optimization and preservation can be determined. Once thought to be a chromosomal aberration associated with absolute sterility, Klinefelter syndrome may now be potentially treatable by testicular sperm retrieval coupled with intracytoplasmic sperm injection. With these therapeutic advances, azoospermic 47,XXY men now may have an opportunity for biological paternity. However, our knowledge of the basic mechanisms underlying germ cell loss and Leydig cell compromise is lagging, and is just now beginning to evolve and provide answers to some of the field's most vexing questions: how to maximize and preserve fertility in Klinefelter males many years or even decades before they wish to actively pursue fatherhood. This article reviews the development of the androgenic and spermatogenic compartments of the Klinefelter testis through puberty, and recommends that it is only with a clear understanding of the basic facts that a rational, considered approach to fertility optimization and preservation can be determined. DiscussYou can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/oatesrd-history-endocrine-function-spermatogenesis-klinefelter-syndrome/ You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/oatesrd-history-endocrine-function-spermatogenesis-klinefelter-syndrome/ Klinefelter syndrome, the most common chromosomal abnormality found in the infertile male population (15% of azoospermic males), occurs at a frequency of 1/600 newborn males, as reviewed by Ghorbel et al. (1Ghorbel M. Gargouri Baklouti S. Ben Abdallah F. Zribi N. Cherif M. Keskes R. et al.Chromosomal defects in infertile men with poor semen quality.J Assist Reprod Genet. 2012; 29: 451-456Crossref PubMed Scopus (32) Google Scholar). There is some thought that the incidence may actually be increasing: a prevalence rise from 1.09 to 1.72 per 1,000 male births (2Morris J.K. Alberman E. Scott C. Jacobs P. Is the prevalence of Klinefelter syndrome increasing?.Eur J Hum Genet. 2008; 16: 163-170Crossref PubMed Scopus (155) Google Scholar). Advancing paternal age may, in part, be causative (3Herlihy A.S. Halliday J. Is paternal age playing a role in the changing prevalence of Klinefelter syndrome?.Eur J Hum Genet. 2008; 16: 1173-1174Crossref PubMed Scopus (7) Google Scholar, 4Herlihy A.S. Halliday J.L. Cock M.L. McLachlan R.I. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison.Med J Aust. 2011; 194: 24-28PubMed Google Scholar). In an adult male who presents with infertility and is found to have a 47,XXY Klinefelter karyotype, the chances of finding sperm during testis tissue extraction are approximately 50% (5Ramasamy R. Ricci J.A. Palermo G.D. Gosden L.V. Rosenwaks Z. Schlegel P.N. Successful fertility treatment for Klinefelter's syndrome.J Urol. 2009; 182: 1108-1113Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 6Schiff J.D. Palermo G.D. Veeck L.L. Goldstein M. Rosenwaks Z. Schlegel P.N. Success of testicular sperm extraction and intracytoplasmic sperm injection in men with Klinefelter syndrome.J Clin Endocrinol Metab. 2005; 90: 6263-6267Crossref PubMed Scopus (236) Google Scholar, 7Schlegel P.N. Nonobstructive azoospermia: a revolutionary surgical approach and results.Semin Reprod Med. 2009; 27: 165-170Crossref PubMed Scopus (72) Google Scholar). There do not seem to be many useful preoperative predictors of successful sperm recovery (8Koga M. Tsujimura A. Takeyama M. Kiuchi H. Takao T. Miyagawa Y. et al.Clinical comparison of successful and failed microdissection testicular sperm extraction in patients with nonmosaic Klinefelter syndrome.Urology. 2007; 70: 341-345Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). There is a suggestion that age may be a factor (9Emre Bakircioglu M. Erden H.F. Kaplancan T. Ciray N. Bener F. Bahceci M. Aging may adversely affect testicular sperm recovery in patients with Klinefelter syndrome.Urology. 2006; 68: 1082-1086Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar), but this possibility should not necessarily be extrapolated to young men or serve as a reason to perform testicular sperm extraction (TESE) with cryopreservation before that boy or man is ready for parenthood, as some investigators have suggested (10Plotton I. Brosse A. Lejeune H. Is it useful to modify the care of Klinefelter's syndrome to improve the chances of paternity? [in French].Ann Endocrinol (Paris). 2010; 71: 494-504Crossref PubMed Scopus (7) Google Scholar). Usually, only a few individual seminiferous tubules are found sprinkled throughout large areas devoid of tubules and replaced by fibrosis and Leydig cell hyperplasia. This ability to treat and help Klinefelter men become fathers has stimulated a resurgence in interest, knowledge, and speculation about all aspects of this chromosomopathy. Diagnosis may be made in several ways: as an unexpected outcome of amniocentesis, during childhood on a workup for existing learning difficulties, at the time of puberty for lack of virilization, during the teenage years after the finding of small testes on physical examination, or during adulthood during the workup of infertility (11Pacenza N. Pasqualini T. Gottlieb S. Knoblovits P. Costanzo P.R. Stewart Usher J. et al.Clinical presentation of Klinefelter's syndrome: differences according to age.Int J Endocrinol. 2012; 2012: 324835Crossref PubMed Scopus (59) Google Scholar). Many men with Klinefelter syndrome, when not diagnosed in childhood, grow and mature to lead healthy, productive lives (12Nielsen J. Johnsen S.G. Sorensen K. Follow-up 10 years later of 34 Klinefelter males with karyotype 47,XXY and 16 hypogonadal males with karyotype 46,XY.Psychol Med. 1980; 10: 345-352Crossref PubMed Scopus (21) Google Scholar). The wide and varied clinical spectrum is well reviewed by Aksglaede et al. (13Abdel-Razic M.M. Abdel-Hamid I.A. Elsobky E. El-Dahtory F. Further evidence of the clinical, hormonal and genetic heterogeneity of Klinefelter syndrome: a study of 216 infertile Egyptian patients.J Androl. 2012; 33: 441-448Crossref PubMed Scopus (17) Google Scholar) in 166 boys, adolescents, and adults with Klinefelter syndrome and by Abdel-Razic et al. (14Aksglaede L. Skakkebaek N.E. Almstrup K. Juul A. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience.Acta Paediatr. 2011; 100: 793-806Crossref PubMed Scopus (112) Google Scholar) in 198 adult Klinefelter males with infertility. It is unknown why a certain male will present on one end of the phenotypic spectrum with failure to virilize while another may actually be quite well androgenized with severe oligospermia. However, research and workshops are under way in an effort to find that answer, whether it be genetic, epigenetic, or a combination, as we still have so much to learn and so many questions to answer (15Juul A. Aksglaede L. Bay K. Grigor K.M. Skakkebaek N.E. Klinefelter syndrome: the forgotten syndrome: basic and clinical questions posed to an international group of scientists.Acta Paediatr. 2011; 100: 791-792Crossref PubMed Scopus (3) Google Scholar). For example, Bojesen et al. (16Bojesen A. Hertz J.M. Gravholt C.H. Genotype and phenotype in Klinefelter syndrome: impact of androgen receptor polymorphism and skewed X inactivation.Int J Androl. 2011; 34: e642-e648Crossref PubMed Scopus (50) Google Scholar) reported that height, arm span, and bone mineral density at the spine and hip were positively correlated with androgen receptor polymorphism in the CAGn repeat, a novel discovery that refuted the thought that these features were all the direct result of simply low levels of testosterone. Efforts are under way to try to increase identification of Klinefelter males as soon as possible to allow intervention at an earlier stage, although it is unknown whether that will necessarily change the course of the disorder. Although this may certainly turn out to be important for the learning difficulties that are part of the Klinefelter phenotype, it is unclear at this time whether early therapeutic involvement in terms of androgen replacement or fertility is helpful or hurtful to the individual. This article briefly summarizes what is understood about testicular function and anatomy in Klinefelter syndrome as regards both the androgenic and spermatogenic compartments. At approximately 5 to 6 weeks after fertilization, primitive bipotential germ cells, having originated in the yolk sac, migrate along the dorsal mesentery to the urogenital ridge, guided directionally by chemotactic signals (17Hughes I.A. Minireview: sex differentiation.Endocrinology. 2001; 142: 3281-3287Crossref PubMed Scopus (93) Google Scholar, 18Magnon C. Lucas D. Frenette P.S. Trafficking of stem cells.Methods Mol Biol. 2011; 750: 3-24Crossref PubMed Scopus (27) Google Scholar). A few weeks later, mesenchymal cells (nascent Leydig cells), interspersed between developing sex cords, begin to secrete testosterone and insulin-like factor 3 (INSL3) while the evolving cohort of Sertoli cells elaborate antimüllerian hormone (AMH). Locally secreted testosterone stimulates morphogenesis of the reproductive ductal division of the ipsilateral mesonephric duct (distal two thirds of the epididymis, vas deferens, seminal vesicle, and ejaculatory duct) while AMH triggers regression of the ipsilateral paramesonephric duct. At a much later stage of embryogenesis and fetal growth, peripheral conversion of testosterone (T) to dihydrotestosterone via 5α-reductase initiates male external genital differentiation and development while INSL3 is required for proper testicular descent (19Ferlin A. Zuccarello D. Zuccarello B. Chirico M.R. Zanon G.F. Foresta C. Genetic alterations associated with cryptorchidism.JAMA. 2008; 300: 2271-2276Crossref PubMed Scopus (104) Google Scholar). Is germ cell migration and testis development normal in the early 47,XXY embryo? The brief answer is that the exodus of 47,XXY gonocytes from the yolk sac and their voyage to the urogenital ridge probably follow a natural path, both temporally and spatially, but this is certainly not known definitively. As reviewed by Lue et al. (20Lue Y.H. Wang C. Liu P.Y. Erkilla K. Swerdloff R.S. Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model.Pediatr Endocrinol Rev. 2010; 8: 140-144PubMed Google Scholar), the XXY mouse model may provide information in this regard. The investigators cited the data of Hunt et al. (21Hunt P.A. Worthman C. Levinson H. Stallings J. LeMaire R. Mroz K. et al.Germ cell loss in the XXY male mouse: altered X-chromosome dosage affects prenatal development.Mol Reprod Dev. 1998; 49: 101-111Crossref PubMed Scopus (65) Google Scholar) who elegantly demonstrated that the number of germ cells that arrive at the genital ridge are typical but that the mitotic proliferation and expansion of their numbers is reduced as the testis develops. This may be due to reactivation of the additional X chromosome when the germ cells reach their destination, but they also concluded that this reduction was related to a defect in Sertoli cell–germ cell communication (21Hunt P.A. Worthman C. Levinson H. Stallings J. LeMaire R. Mroz K. et al.Germ cell loss in the XXY male mouse: altered X-chromosome dosage affects prenatal development.Mol Reprod Dev. 1998; 49: 101-111Crossref PubMed Scopus (65) Google Scholar). In a very tangential way, this thought is supported by Lue et al. (22Lue Y. Liu P.Y. Erkkila K. Ma K. Schwarcz M. Wang C. et al.Transplanted XY germ cells produce spermatozoa in testes of XXY mice.Int J Androl. 2009; 33: 581-587PubMed Google Scholar), who transplanted XY germ cells into 41,XXY murine testes and showed that some of those donor cells could complete spermatogenesis, suggesting that both the XXY germ cell and the XXY environment contribute to impaired spermatogenesis. Parenthetically, even though the nontesticular aspects are not the subject of this review, the mouse model developed by Lue et al. (20Lue Y.H. Wang C. Liu P.Y. Erkilla K. Swerdloff R.S. Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model.Pediatr Endocrinol Rev. 2010; 8: 140-144PubMed Google Scholar) "suggest[s] that the common genes that escape the X inactivation between the XXY mouse and men may be responsible for the clinical manifestations in men with Klinefelter syndrome." This amazing and valuable 41,XXY mouse model is reviewed nicely by Swerdloff et al. (23Swerdloff R.S. Lue Y. Liu P.Y. Erkkila K. Wang C. Mouse model for men with Klinefelter syndrome: a multifaceted fit for a complex disorder.Acta Paediatr. 2011; 100: 892-899Crossref PubMed Scopus (15) Google Scholar). It may be the key to future therapeutic strategies to preserve and/or enhance, if possible, future fertility in the 47,XXY human. Finally, testicular histology (light microscopy) at this stage would be helpful to clarify this issue, but cases of 47,XXY fetal testis examination are extremely limited. Two reports suggest a decrease in germ cell numbers, and two suggest a normal quantitative population (24Coerdt W. Rehder H. Gausmann I. Johannisson R. Gropp A. Quantitative histology of human fetal testes in chromosomal disease.Pediatr Pathol. 1985; 3: 245-259Crossref PubMed Scopus (69) Google Scholar, 25Flannery D.B. Brown J.A. Redwine F.O. Winter P. Nance W.E. Antenatally detected Klinefelter's syndrome in twins.Acta Genet Med Gemellol (Roma). 1984; 33: 51-56PubMed Google Scholar, 26Gustavson K.H. Kjessler B. Thoren S. Prenatal diagnosis of an XXY foetal karyotype in a woman with a previous 21-trisomic child.Clin Genet. 1978; 13: 477-480Crossref PubMed Scopus (13) Google Scholar, 27Murken J.D. Stengel-Rutkowski S. Walther J.U. Westenfelder S.R. Remberger K.H. Zimmer F. Letter: Klinefelter's syndrome in a fetus.Lancet. 1974; 2: 171Abstract PubMed Scopus (26) Google Scholar). Is the androgenic function of the testis normal in the 47,XXY fetus in the later stages of pregnancy? During fetal development, as the testis grows and descends, prenatal levels of testosterone, as measured in amniotic fluid samples at 16 to 20 weeks of gestation, are indeed normal in the 47,XXY fetus as compared with the 46,XY fetus, demonstrating that, at the very least, the androgenic function and output of the fetal 47,XXY testis is adequate (28Ratcliffe S.G. Read G. Pan H. Fear C. Lindenbaum R. Crossley J. Prenatal testosterone levels in XXY and XYY males.Horm Res. 1994; 42: 106-109Crossref PubMed Scopus (41) Google Scholar). At birth, however, many studies show an increased incidence of cryptorchidism (4.5% to 6.3%) and/or microphallus (1% to 4.5%) (29Ratcliffe S.G. The sexual development of boys with the chromosome constitution 47,XXY (Klinefelter's syndrome).Clin Endocrinol Metab. 1982; 11: 703-716Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 30Ross J.L. Samango-Sprouse C. Lahlou N. Kowal K. Elder F.F. Zinn A. Early androgen deficiency in infants and young boys with 47,XXY Klinefelter syndrome.Horm Res. 2005; 64: 39-45Crossref PubMed Scopus (116) Google Scholar), perhaps an indication that there is individual variation and a wide range in fetal testosterone secretion, but the true reasons for these increased rates are not yet known. Lahou et al. (31Lahlou N. Fennoy I. Ross J.L. Bouvattier C. Roger M. Clinical and hormonal status of infants with nonmosaic XXY karyotype.Acta Paediatr. 2011; 100: 824-829Crossref PubMed Scopus (29) Google Scholar) and Lee et al. (32Lee Y.S. Cheng A.W. Ahmed S.F. Shaw N.J. Hughes I.A. Genital anomalies in Klinefelter's syndrome.Horm Res. 2007; 68: 150-155Crossref PubMed Scopus (62) Google Scholar) point out that the overall rate of genital anomalies in infants with Klinefelter syndrome is low and that androgen receptor insensitivity is unlikely to be causative. It is interesting that Zinn et al. (33Zinn A.R. Ramos P. Elder F.F. Kowal K. Samango-Sprouse C. Ross J.L. Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome.J Clin Endocrinol Metab. 2005; 90: 5041-5046Crossref PubMed Scopus (103) Google Scholar) reported an inverse correlation between the androgen receptor CAGn repeat length and penile length, but that the parental origin of the extra X chromosome, imprinting, and skewed X inactivation did not influence the other clinical variables that were assessed. Zeger et al. (34Zeger M.P. Zinn A.R. Lahlou N. Ramos P. Kowal K. Samango-Sprouse C. et al.Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome.J Pediatr. 2008; 152: 716-722Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) also noted reduced penile length in both prepubertal and postpubertal boys. After birth, is the minipuberty normal in the 47,XXY infant? Minipuberty is the term used to describe the neonatal surge of pituitary gonadotropins leading to a temporary rise of testosterone secretion and an increase in absolute Sertoli cell number along with transformation and expansion of the gonocyte pool into Ad spermatogonia (35Zivkovic D. Hadziselimovic F. Development of Sertoli cells during mini-puberty in normal and cryptorchid testes.Urol Int. 2009; 82: 89-91Crossref PubMed Scopus (32) Google Scholar). The exact timing of the peak of this process has not been agreed upon: 2 months (36Forest M.G. Sizonenko P.C. Cathiard A.M. Bertrand J. Hypophyso-gonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy.J Clin Invest. 1974; 53: 819-828Crossref PubMed Scopus (347) Google Scholar, 37Tomlinson C. Macintyre H. Dorrian C.A. Ahmed S.F. Wallace A.M. Testosterone measurements in early infancy.Arch Dis Child Fetal Neonatal Ed. 2004; 89: F558-F559Crossref PubMed Scopus (39) Google Scholar) or 3 to 4 months (38Chada M. Prusa R. Bronsky J. Kotaska K. Sidlova K. Pechova M. et al.Inhibin B, follicle stimulating hormone, luteinizing hormone and testosterone during childhood and puberty in males: changes in serum concentrations in relation to age and stage of puberty.Physiol Res. 2003; 52: 45-51PubMed Google Scholar). As reviewed by Hadziselimovic et al. (39Hadziselimovic F. Zivkovic D. Bica D.T. Emmons L.R. The importance of mini-puberty for fertility in cryptorchidism.J Urol. 2005; 174: 1536-1539Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), dysfunction of any of the components of the minipuberty may underlie the lowered eventual sperm counts in boys with hypogonadotropic hypogonadism by decreasing the number of spermatogonia produced for the future. Therefore, it is of importance to understand whether the minipuberty is normal in its timing and endocrinology in the 47,XXY infant, and if not, whether it can be improved. Studies do agree that testosterone does indeed rise during the minipuberty in 47,XXY infants: low to normal levels as reported by Lahlou et al. (40Lahlou N. Fennoy I. Carel J.C. Roger M. Inhibin B and anti-müllerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome.J Clin Endocrinol Metab. 2004; 89: 1864-1868Crossref PubMed Scopus (127) Google Scholar) in 18 prenatally diagnosed boys and 215 healthy males; normal levels as reported by Aksglaede et al. (41Aksglaede L. Petersen J.H. Main K.M. Skakkebaek N.E. Juul A. High normal testosterone levels in infants with non-mosaic Klinefelter's syndrome.Eur J Endocrinol. 2007; 157: 345-350Crossref PubMed Scopus (70) Google Scholar) in 10 male infants. Aksglaede et al. (42Aksglaede L. Christiansen P. Sorensen K. Boas M. Linneberg A. Main K.M. et al.Serum concentrations of anti-müllerian hormone (AMH) in 95 patients with Klinefelter syndrome with or without cryptorchidism.Acta Paediatr. 2011; 100: 839-845Crossref PubMed Scopus (46) Google Scholar) do, however, demonstrate subtle differences in both Leydig cell and Sertoli cell response in 47,XXY infants, as determined by the luteinizing hormone (LH)/T and follicle stimulating hormone (FSH)/inhibin B ratios as compared with non-47,XXY infants. Sertoli cell function, as determined by AMH secretion, was basically normal as well at this stage. It is interesting that AMH secretion is typically down-regulated in Sertoli cells as they terminally differentiate at puberty (43Rajpert-De Meyts E. Jorgensen N. Graem N. Muller J. Cate R.L. Skakkebaek N.E. Expression of anti-müllerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells.J Clin Endocrinol Metab. 1999; 84: 3836-3844Crossref PubMed Scopus (357) Google Scholar). Cabrol et al. (44Cabrol S. Ross J.L. Fennoy I. Bouvattier C. Roger M. Lahlou N. Assessment of Leydig and Sertoli cell functions in infants with nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are normal and positively correlated with LH levels.J Clin Endocrinol Metab. 2011; 96: E746-E753Crossref PubMed Scopus (62) Google Scholar) also demonstrated that testosterone levels were "normal" but were indeed below the median for controls, hinting at a subtle defect in Leydig cell capacity. Therefore, the hormonal minipuberty dynamics appear to be similar to those found in unaffected infants, with no obvious or dramatic differences. What is known about the spermatogenic compartment in 47,XXY infants? Muller et al. (45Muller J. Skakkebaek N.E. Ratcliffe S.G. Quantified testicular histology in boys with sex chromosome abnormalities.Int J Androl. 1995; 18: 57-62Crossref PubMed Scopus (66) Google Scholar) determined that testicular histology appeared similar in 47,XXY infants compared with 46,XY infants and that the degenerative process in the seminiferous epithelium occurred at a later time. Mikamo et al. (46Mikamo K. Aguercif M. Hazeghi P. Martin-Du Pan R. Chromatin-positive Klinefelter's syndrome: a quantitative analysis of spermatogonial deficiency at 3, 4, and 12 months of age.Fertil Steril. 1968; 19: 731-739PubMed Google Scholar) provided a time frame for this eventuality, concluding that there was a gradual diminution in the number of spermatogonia (24% to 1% of control values) during the first year of life. Because there is such a limited amount of slightly contradictory data, no firm conclusions can be drawn about the number of spermatogonia or their ultimate quality at birth in the 47,XXY infant. Both investigators agree, however, that the number and morphology of the Sertoli cells was normal in the specimens each reviewed. Because the bulk of the testis mass is composed of the seminiferous epithelium and a much smaller percentage by that of the interstitium, it is noteworthy that the prepubertal testicular volume was significantly reduced in 37 boys studied by Zeger et al. (34Zeger M.P. Zinn A.R. Lahlou N. Ramos P. Kowal K. Samango-Sprouse C. et al.Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome.J Pediatr. 2008; 152: 716-722Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) as compared with boys who were normal for that age range, which is as much a reflection of the reduced seminiferous tubule number or diameter as direct histology would be. The pubertal growth spurt timing is essentially the same as in 46,XY boys (47Ratcliffe S. Long-term outcome in children of sex chromosome abnormalities.Arch Dis Child. 1999; 80: 192-195Crossref PubMed Scopus (204) Google Scholar, 48Stewart D.A. Bailey J.D. Netley C.T. Park E. Growth, development, and behavioral outcome from mid-adolescence to adulthood in subjects with chromosome aneuploidy: the Toronto Study.Birth Defects Orig Artic Ser. 1990; 26: 131-188PubMed Google Scholar), although Wikstrom et al. (49Wikstrom A.M. Bay K. Hero M. Andersson A.M. Dunkel L. Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome.J Clin Endocrinol Metab. 2006; 91: 4705-4708Crossref PubMed Scopus (87) Google Scholar) presented data that adolescent 47,XXY boys whose X chromosomes were both maternal in origin entered puberty on average 1.5 years earlier than boys with one maternal and one paternal X chromosome. In combination, three studies by Wikstrom et al. (49Wikstrom A.M. Bay K. Hero M. Andersson A.M. Dunkel L. Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome.J Clin Endocrinol Metab. 2006; 91: 4705-4708Crossref PubMed Scopus (87) Google Scholar, 50Wikstrom A.M. Dunkel L. Wickman S. Norjavaara E. Ankarberg-Lindgren C. Raivio T. Are adolescent boys with Klinefelter syndrome androgen deficient? A longitudinal study of Finnish 47,XXY boys.Pediatr Res. 2006; 59: 854-859Crossref PubMed Scopus (64) Google Scholar, 51Wikstrom A.M. Raivio T. Hadziselimovic F. Wikstrom S. Tuuri T. Dunkel L. Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion.J Clin Endocrinol Metab. 2004; 89: 2263-2270Crossref PubMed Scopus (157) Google Scholar) showed that prepubertal Klinefelter boys have comparable levels of testosterone, FSH, LH, and inhibin B until puberty commences. These findings are supported by Zeger et al. (34Zeger M.P. Zinn A.R. Lahlou N. Ramos P. Kowal K. Samango-Sprouse C. et al.Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome.J Pediatr. 2008; 152: 716-722Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) in their study of 55 boys, and by Bastida et al. (52Bastida M.G. Rey R.A. Bergada I. Bedecarras P. Andreone L. del Rey G. et al.Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome.Clin Endocrinol (Oxf). 2007; 67: 863-870Crossref PubMed Scopus (85) Google Scholar) in their retrospective chart review of 29 Klinefelter adolescents. Bastida et al. (52Bastida M.G. Rey R.A. Bergada I. Bedecarras P. Andreone L. del Rey G. et al.Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome.Clin Endocrinol (Oxf). 2007; 67: 863-870Crossref PubMed Scopus (85) Google Scholar) further conclude, however, that there is evidence in his cohort of mildly impaired Leydig cell function that is evident and demonstrable even in early childhood. In the majority of 47,XXY boys, there is a rise of testosterone through the pubertal years, eventually reaching low normal levels before plateauing and stabilizing (53Salbenblatt J.A. Bender B.G. Puck M.H. Robinson A. Faiman C. Winter J.S. Pituitary-gonadal function in Klinefelter syndrome before and during puberty.Pediatr Res. 1985; 19: 82-86Crossref PubMed Scopus (120) Google Scholar, 54Topper E. Dickerman Z. Prager-Lewin R. Kaufman H. Maimon Z. Laron Z. Puberty in 24 patients with Klinefelter syndrome.Eur J Pediatr. 1982; 139: 8-12Crossref PubMed Scopus (58) Google Scholar). As the pubertal process begins, a somewhat blunted virilization occurs in which the penis elongates, pubic hair develops, erectile capability and libido emerge, but beard growth and muscle development are reduced in comparison with 46,XY counterparts. Because INSL3 is also a Leydig cell product, it is thus a marker of Leydig cell function. Its level does increase in 47,XXY boys at the beginning of puberty (as stimulatory LH rises) at the same rate and magnitude as normal boys until midpuberty where a leveling off occurs (49Wikstrom A.M. Bay K. Hero M. Andersson A.M. Dunkel L. Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome.J Clin Endocrinol Metab. 2006; 91: 4705-4708Crossref PubMed Scopus (87) Google Scholar). In similar fashion, inhibin B reflects Sertoli cell function but with a germ-cell influence from midpuberty onward (55Andersson A.M. Muller J. Skakkebaek N.E. Different roles of prepubertal and postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B levels.J Clin Endocrinol Metab. 1998; 83: 4451-4458Crossref PubMed Scopus (199) Google Scholar). As shown by Andersson et al. (55Andersson A.M. Muller J. Skakkebaek N.E. Different roles of prepubertal and postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B levels.J Clin Endocrinol Metab. 1998; 83: 4451-4458Crossref PubMed Scopus (199) Google Scholar, 56Andersson A.M. Juul A. Petersen J.H. Muller J. Groome N.P. Skakkebaek N.E. Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol levels.J Clin Endocrinol Metab. 1997; 82: 3976-3981Crossref PubMed Scopus (246) Google Scholar), in the 46,XY prepubertal testis, both alpha and beta subunits of inhibin B are manufactured in Sertoli cells, but postpubertally the alpha subunit is still secreted by Sertoli cells while production of the beta subunit is assumed by the germ cells (pachytene to the ea
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