Biology blog Children Fertility genetics

Fertility Rates Among Non-Mosaic XXY; At Odds With Real Life Experience

Klinefelter syndrome (KS) is the one of the most frequent chromosomal disorder affecting 1/500–600 male newborns in the general population. The vast majority of the cases shows the 47,XXY karyotype, although mosaicism (46,XY/47,XXY) or higher-grade X aneuploidies can be rarely detected. Despite its high incidence, KS frequently remains undiagnosed and it is suspected later in adulthood after a diagnostic workup for hypogonadism, couple’s infertility, and/or sexual dysfunction.

Approximately 90% of adult men with homogeneous KS suffer from non-obstructive azoospermia (NOA), while fertility in mosaic KS seems to be less severely affected. Fathering is an important aspect for Klinefelter patients. Maiburg et al. performed a survey on 260 adults with KS and showed that most couples would like to have children and show a positive attitude toward assisted-reproductive techniques (ART). Infertility has been considered an untreatable disease in Klinefelter patients for many years. However, testicular sperm extraction (TESE), associated with ART, were found to be a valuable option for azoospermic men with KS to father a child, due to the presence of residual foci with preserved spermatogenesis

A recent systematic review and meta-analysis evaluated the outcomes of sperm retrieval by conventional TESE (cTESE) and by micro-surgical TESE (mTESE)in 1248 individuals with KS (Corona et al., 2017). Authors reported an average sperm retrieval rate (SRR) of 44% (43% and 45% after cTESE and mTESE, respectively), which is similar to that reported for men without KS. However, these meta-analytic data do not necessarily reflect the rates of SR that physician observe in clinical practice, which is typically lower than 50%. Moreover, results of meta-analysis should be interpreted according to the limitation of the study itself (inclusion of small, single centre studies, effect of un-adjusted confounders).

These meta-analytic data do not necessarily reflect the rates of SR that physician observe in clinical practice, which is typically lower than 50%. Moreover, results of meta-analysis should be interpreted according to the limitation of the study itself (inclusion of small, single centre studies, effect of un-adjusted confounders).

These observations prompted us to conduct a multicenter collaborative study to investigate the rate of and potential predictors of sperm retrieval by TESE in a cohort of azoospermic patients with KS presenting for primary couple’s infertility in the real-life setting.

With the recent improvements of TESE and ICSI procedures infertility has been no longer considered an untreatable disease in Klinefelter patients. In this context, most studies investigating TESE outcomes in patients with KS depicted conflicting results, in spite of having been generally rated of limited quality. A recent review showed that SRR in Klinefelter patients was approximately 50% world wide, thus similar to that of men without genetic abnormalities. However, these results appear to be unrealistic and even far from what physicians typically observe in the clinical practice.

The aim of this cross-sectional, real-life study was to investigate the prevalence of and possible factors associated with a positive SR in a cohort of white-European azoospermic patients with KS undergoing TESE at seven academic Andrology centres.

  • Department of Urology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
  • Division of Experimental Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy
  • Division of Urology; A.O.U. Città della Salute e della Scienza di Torino – Presidio Molinette; Turin, Italy
  • Andrology Unit, University Hospital S. Orsola, Bologna, Italy
  • Fundació Puigvert, Department of Andrology, Universitat Autonoma de Barcelona, Barcelona, Spain
  • Department of Urology and Andrology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
  • Department of Urology, AO Papa Giovanni XXIII, Bergamo, Italy


Of clinical relevance, we found that only one out of five KS men had positive SR in the real-life setting. Moreover, we failed to find any clinical, hormonal or procedural factors associated with SRR. These findings confirmed previous studies, where in contrast meta analytic data reported a significant higher SRR.

So far, there is a lack of reliable clinical and biological predictors for sperm retrieval success in NOA patients with KS. Advanced paternal age has been considered a negative predictive factor for SR in Klinefelter men undergoing TESE. Ozer et al, showed that TESE had better outcome before the critical age of 30.5 years, while other Authors suggested that TESE should be performed before 35 years. Recent evidence, however, support the lack of association between age and SR outcome. It has been shown that performing TESE between 15 and 23 years did not increase the SR rate compared to adult KS patients (25–29 years). We also confirm that SRR was not influenced by patient’s age in a real-life study with a large cohort of Klinefelter men.

According to this view it has been postulated that the progressive hyalinization and fibrosis of seminiferous tubules that is accelerated with the onset of puberty in KS is not ubiquitous and it is possible to observe tubules with normal residual activity. The impaired spermatogenesis could also be caused by an intrinsic problem of the germ cells, possibly linked to (epi)- genetics of the X surplus chromosome.

Testicular volume has been considered a possible factor associated with TESE success in Klinefelter patients, for example, showed that testicular volume was significantly higher in men with positive SRR. However, there are several studies reporting that testicular atrophy does not affect the success of SR (Corona et al., 2017; Franik et al., 2016; Garolla et al., 2018; Majzoub et al., 2016; Ozer et al., 2018; Vicdan et al., 2016). Garolla et al. (Garolla et al., 2018), indeed, observed a 23% SRR even in KS patients with testicles <1 mL. Our results support these findings since we failed to find any relationship between testicular volume and SRR in NOA patients with KS.

The clinical strength of our study is several-fold. First, we showed a low rate of positive sperm retrieval (up to 21%) in azoospermic men with KS in the real-life setting, thus suggesting that the crude data coming from meta-analytic studies cannot be routinely used in the everyday clinical practice.

There are conflicting results showing the association between serum hormones levels and TESE outcome in Klinefelter patients. Higher serum testosterone levels were found in Klinefelter men with positive SR as compared to those with negative SR . Similarly, the combination of high testosterone levels and low levels of LH was considered as positive predictive marker for SR in in both adolescents and adults with KS. Conversely, recent meta analytic data showed that serum hormones levels did not influence SRR in Klinefelter patients. We also showed that testosterone, FSH and LH levels were not different according to TESE outcome in our cohort of Klinefelter patients; however, additional studies are needed to explore the predictive value of serum hormones levels in KS

Testosterone treatment in KS has been previously considered as a negative factor for sperm recovery. In our population TRT was not associated with worse SRR as compared to that of men who did not received any supplementation. Our findings are in line with previous studies that
did not show any impact of testosterone treatment on spermatogenesis in adolescents and adults Klinefelter men. Therefore, some authors did not recommend postponing androgen treatment in adolescent boys with KS for fear of impairing their TESE results .

Lastly, the superiority of mTESE as compared to cTESE in NOA men has been extensively investigated in the previous literature but with conflicting results. This is particularly true also in the Klinefelter population. Only few reports have shown that mTESE could be associated with better SRR than cTESE. Conversely, our results, in agreement with recent studies showed that TESE technique is not associated with SRR.

Further strength of present study is that we have comprehensively investigated a large homogenous group of patients with a detailed hormonal evaluation, and an accurate assessment of possible confounders for impaired semen parameters, such as recreational habits and health comorbidities. However, none of these parameters were found to be associated with SRR.

The clinical strength of our study is several-fold. First, we showed a low rate of positive sperm retrieval (up to 21%) in azoospermic men with KS in the real-life setting, thus suggesting that the crude data coming from meta-analytic studies cannot be routinely used in the everyday clinical practice. Second, we cross-sectionally showed that clinical, hormonal and procedural factors are unable to predict the SRR in patients with KS. In this context, we believe that Klinefelter patients should be carefully counselled regarding their chance of retrieving spermatozoa after TESE. Further strength of present study is that we have comprehensively investigated a large homogenous group of patients with a detailed hormonal evaluation, and an accurate assessment of possible confounders for impaired semen parameters, such as recreational habits and health comorbidities. However, none of these parameters were found to be associated with Sperm Retrieval Rates.

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