Klinefelter Syndrome in Adolescence - The Journal of Clinical ...

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2266 J Clin Endocrinol Metab, May 2004, 89(5):2263–2270 Wikström et al. Testicular Degeneration in Adolescent KS Boys FIG. 1. Testicular biopsies of five adolescent boys with KS from list in Table 1 and one normal boy. Stain, Toluidine blue. A, Patient 4, two types of seminiferous tubules identifiable: those with no spermatogonia on the right and those with spermatogonia of adult pale type (Ap) on the left. Ad, Spermatogonia of adult dark type. Sertoli cells, Sa and Sb type; Leydig cells, juvenile type, some hyperplasia; interstitium, increased fibrosis (magnification, 400). B, Patient 8, no spermatogonia. Sertoli cells, Sa and Sb type; Leydig cells, juvenile type. Interstitial compartment appears normal (magnification, 400). C, Patient 12, no spermatogonia. Sertoli cells, Sa and Sb type, pale and degenerative. Interstitial compartment has increased volume, hyperplastic Leydig cells, and some fibrosis (magnification, 400). D, Patient 14, seminiferous tubules completely hyalinized. Interstitial compartment has hyperplastic Leydig cells and extensive fibrosis (magnification, 400). E, Patient 7, centrally seminiferous tubules with Ap and/or Ad spermatogonia. This area is surrounded by tubules in which the degeneration process is evident: tubules with pale degenerative Sertoli cells and small tubules with dark small apoptotic cells (magnification, 200). F, Normal control, age 11 yr, testicular biopsy taken at surgical exploration because of scrotal pain (magnification, 200).
Wikström et al. Testicular Degeneration in Adolescent KS Boys J Clin Endocrinol Metab, May 2004, 89(5):2263–2270 2267 FIG. 2. Patient 2, group I (Table 1). Electron micrograph of testicular biopsy of boy with KS at age 10.1 yr and Tanner stage P1G1. Undifferentiated Sertoli cells resembling Sa type with a round nucleus with a small nucleolus lacking lamellar body and with crystalloids from Charcot-Bötscher. In the center, one degenerating Sertoli cell (magnification, 2500). testosterone had reached 2.5 nmol/liter, a marked drop in serum AMH had already occurred (Fig. 4B). Discussion With the aid of modern infertility treatment technologies such as ICSI, some men with KS may father children. However, in adulthood, when these treatments come into consideration, the testes of most KS men are completely atrophied. In the current work we investigated whether adolescent patients with KS have germ cells and evaluated whether early puberty is the optimal period for retrieving germ cells for further use in ICSI. Although this concept has gained further actuality with the recent report of a successful extraction of sperm-containing tissue from a 15-yr-old boy with KS (20), it has not been previously investigated systematically. We found, surprisingly, that in early adolescence as many as 50% of the boys with KS had germ cells in their testes and that the depletion of these cells accelerated at the onset of puberty. This presence of germ cells during peripuberty contrasts with results of a report by Müller et al. (5), in which no germ cells were detectable in KS boys beyond the age of 2 yr. A probable explanation is that all boys in Müller’s publication were cryptorchid, whereas none in our group had any history of testicular maldescendent. Cryptorchidism is known to cause marked decrease in germ cell numbers also in boys with a normal karyotype (21, 22). Ad spermatogonia that develop postnatally from fetal spermatogonia under gonadotropin and testosterone stimulation are of fundamental importance for the development of male fertility (23). In the boys with KS, the fact that the number of these cells was markedly reduced indicates a severely impaired fertility potential even in early puberty. Furthermore, we observed only type A spermatogonia in our boys with KS, which suggests an arrest in germ cell development at the stage of A spermatogonia. Normally, type A spermatogonia transform into type B spermatogonia and further to the first primary spermatocytes at the age of 5 yr (18, 24). At present, whether this defect in spermatogenesis in the XXY testis is intrinsic to germ cells or due to the inability of the Sertoli cells to support normal germ cell development is unknown. A defect in Sertoli and germ cell communication in the differentiating XXY testis has been suggested (25). Activation of the hypothalamic pituitary testicular axis was associated with depletion of germ cells. A strong correlation appeared between an increasing testosterone level and suppression of the Sertoli cell markers inhibin B and AMH. It is possible that the molecular mechanisms induced by the altered dosage of X-encoded genes in testicular cells may accelerate loss of germ cells. For example, the androgen receptor gene is located on the X chromosome (26). The testicular volume of KS boys is already below normal during childhood (1.0–1.5 ml; normally 1.8 ml) (27, 28). During puberty their testes grow (11, 12), which was also observed in the current work (Figs. 3 and 5). In healthy boys, the proliferation of germ cells is predominantly responsible for the pubertal growth of the testes (29, 30). Because we could detect no spermatogenesis beyond the development of type A spermatogonia and the number of these cells was low, the pubertal testicular growth in KS boys was due almost solely to the proliferation of Sertoli cells and interstitial cells. This might suggest that the immature Sertoli cells of boys with KS are responding to the pubertal increase in FSH stimulation, as seen in boys with a normal karyotype. On the other hand, the prepubertal Sa and Sb cells were not capable of transforming into the adult Sc cell type, and the degeneration of Sertoli cells increased markedly during puberty. It is therefore tempting to hypothesize that the regression of the testes in KS includes Sertoli cell degeneration. Consistently, electron microscopy revealed degenerating Sertoli cells, a rare finding in testes of healthy early pubertal boys. The concept of Sertoli cells in boys with KS regressing after the initial phase of Sertoli cell proliferation during early puberty is in agreement with changes observed in serum levels of inhibin B (31). This glycoprotein is thought to reflect Sertoli cell function during prepuberty and become germ cell dependent during midpuberty (32). In our cohort of boys with KS, serum inhibin B levels during prepuberty and early puberty were normal (33–35), and measurable inhibin B levels did not fully correlate with the presence of germ cells in the testes. This suggests that during early puberty, serum inhibin B levels in boys with KS reflect the integrity or number of Sertoli cells or both. A normal inhibin B level and a low testosterone level were also shown to be inconsistent with the presence of spermatogonia (group IIA in Tables 1 and 2 and Fig. 4A). AMH or Müllerian-inhibiting substance, a glycoprotein dimer of the TGF family, is expressed in prepubertal but not adult Sertoli cells (36). Serum AMH levels remain high
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