Fertility Assessment in Patients With Klinefelter Syndrome
Fertility Assessment in Patients With Klinefelter Syndrome
Klinefelter syndrome is characterized by primary testicular failure and progressive
 infertility. The objective of this study is to determine if sperm are present and can be
 observed in semen samples of adolescent and young adult Klinefelter patients and to determine
 whether the presence of sperm correlates with physical and/or clinically obtained hormone
 measures of pubertal development.

 This study was designed in order to answer the following questions:

 1. Is it possible to retrieve sperm for cryopreservation from semen samples of adolescent
 and young adult Klinefelter patients?

 2. Does the presence of sperm correlate with the physical and/or endocrine measures that
 are assessed during routine clinical evaluations of pubertal development in the KS
 patient population?

 3. If sperm retrieval is possible, what is the optimal age at which sperm retrieval should
 be attempted?
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.