Advanced Paternal Age May Reduce Sperm Retrieval Success in Nonmosaic Klinefelter Syndrome: Study
IMAGE: HUMAN SPERM STAINED FOR SEMEN QUALITY TESTING IN THE CLINICAL LABORATORY. view more
CREDIT: ©BOBJGALINDO
Klinefelter syndrome is the most common sex chromosomal disorder in patients assigned male gender at birth. The initial description included ‘‘bilateral gynecomastia, small testes, aspermatogenesis,’’ features that remain pathognomonic for this condition. Subsequent studies genetically defined Klinefelter syndrome as the presence of 1 or more additional X chromosomes, most commonly a 47,XXY genotype. More recently, there has been an effort to delineate patients with more than 1 additional X chromosome (such as 48,XXXY and 49,XXXXY) from 47,XXY patients. Although the hormonal aberrations and testicular histology are similar, those with more than 1 additional X chromosome may experience more significant cognitive disabilities, congenital malformations, and medical problems. Although some patients with Klinefelter syndrome exhibit genetic mosaicism, the true prevalence of mosaic Klinefelter syndrome is likely underreported given that many mosaic men with milder phenotypes remain undiagnosed.
Nearly all men with nonmosaic Klinefelter syndrome are azoospermic due to spermatogonial stem cell apoptosis. Focal spermatogenesis can still occur, potentially due to stochastic loss of the additional X chromosome in rare spermatogonial stem cells, although other theories for focal spermatogenesis in men with Klinefelter syndrome also exist. Regardless of the mechanism of spermatogenesis, some men with Klinefelter syndrome can achieve biological paternity with surgical sperm retrieval followed by intracytoplasmic sperm injection (ICSI).
It remains controversial at what age patients with Klinefelter syndrome should undergo sperm retrieval via testicular sperm extraction (TESE). If a patient is diagnosed prenatally or in adolescence, some providers have advocated for sperm retrieval soon after puberty to avoid the presumed decline in spermatogenic potential over time due to progressive germ cell apoptosis and hyalinization of seminiferous tubules.
When considering the timing of TESE, there may be harm done by attempting to retrieve sperm in adolescent boys who may not be able to provide their own informed consent or assent for this procedure. Additionally, some of these patients may ultimately never choose to pursue fatherhood and thus would be subjected to unnecessary surgery. On the other hand, it is possible that men with Klinefelter syndrome may experience progressive loss of rare euploid spermatogonial stem cells and subsequently miss a window for biological fatherhood, or that a negative sperm retrieval in late adolescence may alleviate some of the uncertainty surrounding their ability to become a biological father.
Authors hypothesized that adolescents with Klinefelter syndrome may safely delay sperm retrieval until adulthood. In this systematic review and meta-analysis, they characterized the available literature on surgical sperm retrieval performed in patients with nonmosaic Klinefelter syndrome. Authors included studies reporting outcomes from both conventional TESE (cTESE), and microdissection TESE (mTESE). The primary outcome of interest was surgical sperm retrieval success rate in adolescent vs. reproductive-aged males.
Studies were included if they reported outcomes from conventional or microdissection testicular sperm extraction in patients with nonmosaic (47,XXY) KS. Extracted data included age and number of participants, sperm retrieval rate (SRR), live birth rate (LBR), total testicular volume, preprocedural testosterone, blood follicle-stimulating hormone, and luteinizing hormone levels.
Forty eight studies were included with a total of 2,815 participants and a median SRR of 44%. Sensitivity analyses determined a low risk of bias. Nine studies or subgroups of studies analyzed adolescent participants with a mean age <20 years. Of 48 studies, 24 reported findings for groups of patients with positive sperm retrieval compared to negative sperm retrieval. Metaanalysis estimated that groups with positive sperm retrieval were on average 2.8 years younger than groups with negative sperm retrieval (95% confidence interval: − 3.62 to − 2.02 years; I 2 = 78%). There was no difference in the mean SRR between adolescent and adult cohorts (45% vs. 42%) across all studies. There was a nonsignificant quadratic relationship between age and SRR, potentially suggesting that sperm retrieval outcomes may decline after 40 years of age. Twenty-two studies reported LBRs with an overall median of 11.1%.
In this meta-analysis of patients with nonmosaic Klinefelter syndrome, authors found no difference between surgical sperm retrieval success in adolescence compared with reproductive adulthood. The limited data available for patients 40 and older suggest that SRR may wane beyond age 40, but additional studies are needed to evaluate this possible trend. Nevertheless, on the basis of the available studies, sperm retrieval can be delayed until early adulthood but should be completed expediently once reproductive goals are determined. Patients should be carefully counseled not only on surgical sperm retrieval success (approximately 50%), but also the attrition that occurs with assisted reproductive technology and the modest live birth rates seen in the studies aggregated in this meta-analysis. It may be reasonable to offer a semen analysis in postpubertal males and pursue cryopreservation if sperm are identified, although this would be unlikely. Given the nuances of recovering sperm in patients with Klinefelter syndrome, along with the increased prenatal diagnosis of Klinefelter syndrome, multidisciplinary care is recommended, including urologists, endocrinologists, social workers, and others, to ensure the best care is provided to these patients from infancy through adulthood.
Source: Leila Momtazi-Mar, Bryan D. Naelitz, Andrea Mucci; Fertil Steril® Vol. 124, No. 6, December 2025
