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

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-