Fertility Assessment in Patients With Klinefelter Syndrome

Klinefelter Syndrome (KS) is a genetic condition in boys and men that results from having two
X chromosomes and one Y chromosome. The incidence of the 47, XXY karyotype that defines the
disorder ranges from 1:500 to 1:1000 in newborn males. The sexual development and fertility
phenotypes of Klinefelter's syndrome include azoospermia (absence of sperm in the ejaculate),
small firm testes, gynaecomastia (enlargement of breast tissue), low testosterone levels, and
elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels that can have
an important impact on the quality of life for these patients. Beginning with puberty,
testicular biopsies from Klinefelter patients progressively show a degenerated testicular
environment with Sertoli-cell-only tubules, sclerotic or hyalinized tubules, and interstitial
Leydig cell hyperplasia. Nevertheless, scattered areas with focal spermatogenesis can be seen
in Klinefelter men, and assisted reproductive techniques now offer hope for patients who wish
to father their own biological children. In these cases, a surgical sperm recovery procedure
called testicular sperm extraction (TESE) is performed to extract sperm for in vitro
reproductive methods. Success rates for testicular sperm extraction in Klinefelter patients
are consistently above 50% (50 - 72%) and are similar to the success rates reported for TESE
in azoospermic patients without Klinefelter syndrome. Pregnancy rates and life births after
intracytoplasmic sperm injection (ICSI) are similar in couples with or without KS, and babies
fathered by KS patients have a normal karyotype. Previous studies in adult KS patients
reported that sperm recovery rates were significantly lower after the age of 35. Therefore,
it was suggested that surgical sperm recovery in younger (possibly pubertal) boys should be
considered as an option to maximize the opportunity to preserve their fertility before
becoming sterile. However, there is considerable debate about the benefit of early invasive
fertility intervention for KS patients.

The standard, non-invasive and safe way to obtain and analyze sperm production and quality in
normal post-pubertal males is to obtain a semen sample by masturbation. It is currently
unknown when spermatogenesis starts in boys with KS, and if sperm could be detected by semen
analysis in early puberty. In this proposal, the investigators aim to determine if
non-invasive methods during puberty could be useful to assess the reproductive potential of
KS patients, and to possibly cryopreserve sperm from these patients for future use with
well-established assisted reproductive techniques like in vitro fertilization with ICSI
(intra cytoplasmic sperm injection).

Although this will be a sensitive topic for adolescent patients with KS and their parents, it
is essential to begin the conversation regarding fertility preservation. Indeed, most parents
and patients have questions regarding future fertility. This study has a secondary benefit in
that it provides an ideal opportunity to educate the affected males and their families about
the long-term effects of KS on their fertility and the availability of reproductive
technologies to help with fertility. Similar discussions are becoming increasingly common
(standard of care) for cancer patients who are at risk for infertility due to their disease
or oncologic treatment.

It is currently unknown when spermatogenesis starts in boys with KS. While it seems to be
commonly accepted that there is a progressive depletion of germ cells in the testes of KS
patients after the onset of puberty, the data to support this notion are equivocal due to
small patient populations, lack of controls and absence of longitudinal data.

In addition, the standard therapy for boys with KS is testosterone replacement therapy to
trigger entry and progression of puberty characterized by the development of secondary sexual
characteristics, bone maturation, and continued linear growth. However, testosterone
supplementation also suppresses spermatogenesis (if present) through negative feedback on the
hypothalamus-pituitary-gonadal axis. Some argue that any intervention to preserve fertility
for KS patients should ideally precede hormone replacement therapy. However, in one study it
was proposed that topical testosterone therapy might not negatively affect spermatogenesis in
adolescent KS patients. The risks and unknowns of invasive surgical procedures like TESE for
boys have to be carefully weighed against the possible benefits for this unique patient
population. For these reasons, the investigators propose that non-invasive methods would be
appropriate to retrieve sperm and are essential to gain insights about the initiation and
decline of spermatogenesis in KS patients.

In this study, the investigators will analyse if sperm can be found in semen of Klinefelter
patients during puberty and early adulthood. Participants will be followed until they reach
age 26. During the time of their study participation, participants will provide at least one
semen sample.

Inclusion Criteria:

- males between the ages of 12 and 25

- diagnosed with mosaic or non-mosaic Klinefelter's Syndrome

- having bilaterally descended testes

- not having had a febrile illness within 3 months of enrollment.

Exclusion Criteria:

- previous treated with gonadotoxic chemotherapeutic or radiation regimen.

- psychological, psychiatric, or other conditions which prevent giving fully informed
consent.