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

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2268 J Clin Endocrinol Metab, May 2004, 89(5):2263–2270 Wikström et al. Testicular Degeneration in Adolescent KS Boys FIG. 3. A, Testicular volumes and serum FSH, testosterone, inhibin B, and AMH levels in 14 boys with KS with spermatogonia present or absent in the biopsy specimen (n 7, both groups). Horizontal lines, 10th, 25th, 50th, 75th, and 90th percentiles, and extreme values are shown separately. B, Longitudinal changes in individual testis volumes. Black circles, group I, white circles, group II (see Table 1). FIG. 4. A, Longitudinal changes in inhibin B, testosterone, and AMH concentrations in 14 boys with KS. B, Correlations between inhibin B and testosterone and AMH and testosterone. Dashed lines, serum testosterone 2.5 nmol/liter. Black circles, group I; white circles, group II (see Table 1).
Wikström et al. Testicular Degeneration in Adolescent KS Boys J Clin Endocrinol Metab, May 2004, 89(5):2263–2270 2269 FIG. 5. Distributions of serum FSH, LH, testosterone, inhibin B, and AMH concentrations and testicular volume in 14 boys with KS followed up during puberty. Tanner G stages. There were 22–32 observations at stage G1, 13–21 observations at G2, 14–16 observations at G3, and five to six observations at G4. Horizontal lines, 10th, 25th, 50th, 75th, and 90th percentiles, and extreme values are shown separately (white circles). throughout childhood and wane at puberty (37). We observed high AMH values in KS boys during prepuberty and early puberty, followed by a decline as serum testosterone increased: the timing and magnitude of this decrease was similar to that in normal boys (37, 38) and in agreement with the inverse correlation between serum AMH and testosterone during normal puberty (38). It has been proposed that the dramatic suppression of AMH production requires meiotic entry in spermatogenesis (39). Rajpert-De Myets et al. (40) in their 1999 study noted, however, that the switch in AMH expression occurred also in adolescent boys without germ cells. Our observations, being consistent with these findings, suggest that meiotic activity is unnecessary for down regulation of AMH expression (Table 2). The decrease in serum AMH levels thus cannot serve as an indicator of spermatogenetic activity in KS boys because the biopsy specimens of the boys with low AMH values showed no spermatocytes (group IIB, Tables 1 and 2). We obtained only a single biopsy from each subject, but even in these very small specimens, we could demonstrate the focal nature of the seminiferous epithelium degeneration (Fig. 1E), perhaps explaining the fact that some adult men with KS display areas of spermatogenesis. It is possible that in our work such areas or their predecessors may have escaped detection. In adult subjects with KS, the success rate for obtaining spermatozoa with sperm-containing tissue is currently at least 50% (41), but multiple testicular biopsies are always required for successful sperm recovery (42). We therefore hypothesize that if several biopsies had been performed, more germ cells would have been found in our subjects. The diagnosis of infertility in KS boys cannot be made on the basis of only one biopsy. These issues were thoroughly discussed with the boys and their parents. Only a minority of subjects with KS is diagnosed before puberty (2). Later the condition may come to attention during evaluation of hypogonadism and infertility. In the current work, all boys were diagnosed prepubertally, and 13 of 14 patients initially presented with language and behavioral problems. We cannot formally exclude the possibility that these boys differ from other KS subjects in terms of fertility prognosis. However, to our knowledge there is no evidence in the literature indicating that early neurological problems in KS are related to testicular function. The possible future use of the cryopreserved testicular samples of KS patients in infertility treatments most probably requires in vitro maturation of spermatogonia into mature spermatozoa or at least into late/elongated spermatids. Recent studies (43, 44) indicate that human testicular tissue can be cultured for at least up to 3 wk without essential loss of spermatogonia. Early results also suggest that meiosis and spermatogenesis may resume under culture conditions, yielding normal spermatids with some fertilizing potential (44). In conclusion, we investigated whether early adolescence is a suitable time period in life for obtaining germ cells for future infertility treatment in subjects with KS. Our results show that early adolescent boys with KS have testicular germ cells that display a maturational arrest at the level of type A spermatogonia. No meiotic cells were detected in any of the biopsy specimens, and onset of puberty was associated with depletion of spermatogonia. Based on these results, it seems that early puberty does not provide an unique window of opportunity to increase fertility potential of subjects with KS. Future research is thus required to elucidate the mechanisms activated at puberty that ultimately lead to hypogonadism characteristic for the syndrome. Acknowledgments Received October 3, 2003. Accepted February 10, 2004. Address all correspondence and requests for reprints to: Leo Dunkel, Hospital for Children and Adolescents, University of Helsinki, P.O. Box 281, 00029 Helsinki, Finland. E-mail: leo.dunkel@hus.fi. This work was supported by grants from the Medical Society of Finland (Finska Läkaresällskapet) (to A.M.W.), the Mjölbolsta Founda-
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