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.