Surgery retrieves sperm in 44% of cycles in Klinefelter syndrome
Surgery found sperm in 44% of attempts in men with Klinefelter syndrome, a 2017 meta-analysis of 37 observational studies found. Age, testis size and hormone levels did not change the retrieval rate. About 4 out of 10 ICSI cycles using that sperm ended in a live birth.
Key Findings
Across 37 studies and 1248 men with Klinefelter syndrome, sperm retrieval succeeded in 44% of testicular sperm extraction (TESE) cycles (95% CI 39 to 48%).
Conventional TESE retrieved sperm in 43% of cycles (35 to 50%) and microsurgical TESE in 45% (38 to 52%). Per patient, the retrieval rate was 45% (40 to 51%).
Studies enrolling men under 20 years and studies of the rest of the sample each found a 43% retrieval rate (P = 0.95).
In 29 studies, the pooled pregnancy rate after ICSI was 43% per cycle (36 to 50%). The live birth rate was 43% per cycle (34 to 53%).
Fresh and cryopreserved sperm gave similar live birth rates per ICSI cycle: 39% (23 to 57%) and 29% (17 to 44%), P = 0.38.
Interpretation
The paper pools group averages from 37 observational studies. Twenty were prospective and 17 retrospective, so the pooled rates rest on observational data. The authors had no patient-level data and could not exclude some selection bias from the retrospective studies or the effect of unadjusted confounders. They call for confirmation in larger trials. All but two studies enrolled non-mosaic Klinefelter syndrome. Too few studies reported testosterone treatment, the woman's age or chromosome findings in the children to test them. Higher FSH showed a possible link to lower live birth rates (P = 0.06).
RRM Context
The authors note that most cases of Klinefelter syndrome go undiagnosed. Men often learn of it during a couple's infertility evaluation. A chromosome cause of azoospermia (no sperm in the semen) gets a name only when the man is evaluated. Restorative reproductive medicine evaluates both partners from the start. The pregnancy figures come from ICSI, which bypasses the sperm-production problem and leaves it unresolved.
Our editorial summary of this paper, not the article's abstract.
Abstract
Background
Specific factors underlying successful surgical sperm retrieval rates (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in adult patients with Klinefelter syndrome (KS) have not been completely clarified.
Objective and Rationale
The aim of this review was to meta-analyse the currently available data from subjects with KS regarding SRRs as the primary outcome. In addition, when available, PRs and live birth rates (LBRs) after the ICSI technique were also investigated as secondary outcomes.
Search Methods
An extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR for conventional-TESE (cTESE) or micro-TESE (mTESE) and its specific determinants without any arbitrary restriction were included.
Outcomes
Out of 139 studies, 37 trials were included in the study, enrolling a total of 1248 patients with a mean age of 30.9 ± 5.6 years. The majority of the studies (n = 18) applied mTESE, 13 applied cTESE and in one case testicular sperm aspiration (TESA) was used. Additionally, four studies used a mixed approach and in one study, the method applied for sperm retrieval was not specified. Overall, a SRR per TESE cycle of 44[39;48]% was detected. Similar results were observed when mTESE was compared to cTESE (SRR 43[35;50]% vs 45[38;52]% for cTESE vs micro-TESE, respectively; Q = 0.20, P = 0.65). Meta-regression analysis showed that none of the parameters tested, including age, testis volume and FSH, LH and testosterone (T) levels at enrollment, affected the final SRR. Similarly, no difference was observed when a bilateral procedure was compared to a unilateral approach. No sufficient data were available to evaluate the effect of previous T treatment on SRR. Information on fertility outcome after ICSI was available for 29 studies. Overall a total of 218 biochemical pregnancies after 410 ICSI cycles were observed (PR = 43[36;50]%). Similar results were observed when LBR was analyzed (LBR = 43[34;53]%). Similar to what was observed for SRR, no influence of KS age, mean testis volume, LH, FSH or total T levels on either PR and LBR was observed. No sufficient data were available to test the effect of the women's age or other female fertility problems on PR and LBR. Finally, no difference in PR or LBR was observed when the use of fresh sperm was compared to the utilization of cryopreserved sperm.
Wider Implications of the Findings
The present data suggest that performing TESE/micro-TESE in subjects with KS results in SRRs of close to 50%, and then PRs and LBRs of close to 50%, with the results being independent of any clinical or biochemical parameters tested.
Mazzilli R et al., 2026·Journal of endocrinological investigation
Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion.
to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies.
this narrative review included all available articles, published up to January 2026.
Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
Ponce MR et al., 2026·Andrology·Free full text on PubMed Central
Transgender individuals assigned male at birth (AMAB) may choose to preserve their fertility prior to starting gender-affirming hormone therapy (GAHT). However, limited data exist regarding the baseline reproductive and hormonal characteristics of this population before and after GAHT.
To characterize semen quality and hormonal profiles in transgender AMAB individuals prior to GAHT and compare findings with cisgender men and with transgender individuals who discontinued GAHT for at least 3 months.
This retrospective study included transgender AMAB individuals from two tertiary andrology centers who underwent sperm cryopreservation before GAHT initiation (treatment-naïve group). Clinical evaluation included anthropometric measures, testicular volume assessment, varicocele detection, and sex hormone measures. Semen parameters were analyzed according to WHO criteria and compared with those of cisgender men and previously treated transgender individuals.
Thirty-two treatment-naïve transgender AMAB individuals were included. Hormonal parameters were generally within reference ranges. Only 46.9% of treatment-naïve individuals met WHO criteria for normozoospermia, compared with 75.5% of cisgender controls. Compared with nine previously treated individuals, estradiol levels were higher and seminal volume lower. A higher frequency of seminal abnormalities was observed, although not statistically significant.
A substantial proportion of treatment-naïve transgender AMAB individuals exhibited impaired semen parameters prior to GAHT initiation. Prior GAHT exposure showed a trend toward poorer semen quality. These findings support early fertility counseling and preservation in transgender individuals prior to GAHT initiation.
Besides gonadal involvement (hypogonadism, male factor infertility, and testicular hypotrophy), patients with Klinefelter syndrome (KS) may suffer from several extra-gonadic complications, including neoplastic events.
The aim of this review is to summarize all major clinical evidence dealing with the association between KS and neoplastic diseases and provide practical suggestions for the management of patients with KS regarding neoplastic risk.
This narrative review was conducted through a comprehensive search of the PubMed database, using combinations of the following keywords: "Klinefelter syndrome," "cancer," "neoplasm," "breast cancer," "germ cell tumor," "lymphoma," and "testosterone replacement therapy".
KS is associated with a higher risk of breast cancer and mediastinal germ cell tumors and an apparent higher risk of hematological malignancies, in particular non-Hodgkin lymphoma and leukemia. Evidence on testicular cancer is limited, with no clear increase in risk attributable to KS, while prostate cancer has a lower risk and lower mortality rate.
Given the complexity of the syndrome and the limited available evidence, regular clinical follow-up with targeted investigations when clinically indicated may facilitate early diagnosis and management of associated comorbidities.
Scala A et al., 2026·Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA·Free full text on PubMed Central
In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4-0.6 SD, with male references identifying more individuals with low BMD for age, especially in those assigned male at birth. Dual-reference reporting is advisable until further evidence becomes available.
Transgender individuals, especially those assigned male at birth (AMAB), exhibit lower bone mineral density (BMD) compared with the cisgender population. Interpretation of densitometric data is challenging, as the choice of reference gender can significantly influence Z-scores and fracture risk scores. This study aims to evaluate the impact of the gender reference database (male or female) on the assessment of BMD and fracture risk in transgender adults prior to gender-affirming hormone therapy (GAHT).
We conducted a cross-sectional analysis of 249 transgender individuals (153 assigned female at birth - AFAB and 96 AMAB) aged 18-43 years, recruited in the Hospitals of Padua and Brescia (Italy). Z-scores were calculated using both male and female reference databases and FRAX scores were computed using both gender inputs. Associations with anthropometric, biochemical, and hormonal parameters were explored.
Z-scores differed systematically depending on the reference gender, with mean ΔZ ranging 0.4-0.6 SD across skeletal sites. Switching reference databases frequently led to reclassification of BMD status. AMAB individuals showed a higher prevalence of low BMD for age, particularly when assessed against male references (27.1%), whereas AFAB participants generally maintained normal BMD. However, FRAX scores remained low. BMI and 25-OH vitamin D levels were independent predictors of BMD and Z-scores in AMAB individuals.
The choice of reference gender significantly influences densitometric interpretation in young transgender adults. Until further evidence becomes available, calculating Z-scores using both male and female reference databases is advisable. Early preventive interventions remain essential to preserve bone health.
Related research
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
To investigate whether sperm recovery is related to clinical features, hormone parameters and testosterone replacement therapy (TRT) in patients with Klinefelter syndrome (KS).
This study provides three interesting insights: (i) the probability to retrieve sperm is not related to testicular volume; (ii) TRT does not affect sperm retrieval rate (SRR); and (iii) reduced levels of LH and FSH represent a negative predictor of sperm retrieval in patients with TRT.
Classical KS shows a karyotype with one extra X chromosome in all of somatic cells and clinical manifestations characterized by hypergonadotropic hypogonadism and infertility.
STUDY DESIGN, We performed a retrospective cohort study. Data from 111 consecutive KS azoospermic patients undergoing testicular sperm extraction (TESE) were collected from 2005 to 2016.
PARTICIPANTS/MATERIALS, Data on anthropometric parameters, reproductive hormones and testicular volumes were collected. SRR was related to clinical characteristics and compared between TRT and untreated patients.
MAIN A total of 38 patients (34.2%) had successful sperm recovery. The comparison of clinical characteristics did not differ between patients with and without sperm recovery. Sperm retrieval was successful also in subjects with smaller testes. The comparison of SRR in patients with or without TRT was not different (33.3% vs 34.6%). In TRT group, LH and FSH levels were significantly lower in subjects with no sperm retrieval (P values, respectively, <.05 and <.001).
LIMITATIONS Well-designed controlled studies are necessary to confirm these data aimed to set the best therapeutic approach for fertility management in hypogonadal patients with nonmosaic KS.
Age at TESE, anthropometric measures, testis volume, sex hormones levels and semen parameters are not predictive parameters of SRR. Among TRT patients, reduced gonadotropin is related to failure in sperm retrieval.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Selice R et al., 2010·Journal of endocrinological investigation
Klinefelter syndrome (KS) (47,XXY) is the most common sex chromosomal disorder, and it is a frequent form of male hypogonadism and infertility. Although the majority of these patients are azoospermic, they might have severe oligozoospermia or residual single-residual foci with spermatogenesis in the testis.
We report our experience on sperm retrieval in the ejaculate and testis, and evaluate the frequency of chromosome abnormalities in sperm of KS.
Eighty-four 47,XXY KS were evaluated with seminal analysis, body hair distribution, reproductive hormones, ultrasonographic scanning of the testis and prostate, bilateral testicular sperm extraction (TESE), sperm or testicular cells sex chromosomes aneuploidies.
Out of 84 patients, 7 (7/84; 8.3%) had sperm in the ejaculate. Out of the 77 azoospermic patients, 24 underwent TESE and 9 (9/24; 37.5%) had successful sperm recovery. The comparison of reproductive hormones, age and testicular volume did not show significant differences between patients with and without successful sperm recovery in semen or TESE . Patients without successful sperm recovery in semen analysis or TESE had signs of hypoandrogenism more evident than patients with successful sperm recovery. Patients with KS produced a higher number of sperm aneuploidy with respect to normozoospermic fertile controls and non-genetic severely oligozoospermic men.
Men with KS are not always sterile. In some of these patients sperm can be found in semen or in the testis, but the proportion of sperm aneuploidy is high. Signs of hypoandrogenism seem to be associated with low sperm recovery rate.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Genetic variability within the follicle-stimulating hormone (FSH)-related genes might contribute to phenotypic heterogeneity in patients with Klinefelter syndrome (KS), yet its clinical impact on sperm retrieval remains unclear.
To investigate the association between FSHB c.211 G > T and FSHR polymorphisms (c.2039 A > G and c.29 G > A) and hormonal parameters, as well as their potential role in predicting sperm retrieval rate (SRR) in patients with KS undergoing testicular sperm extraction (TESE).
A retrospective cohort of patients with KS was analyzed. Only subjects not receiving testosterone replacement therapy were included (n = 417). Hormonal, anthropometric, and clinical variables were compared across genotypes using nonparametric tests. Additive genetic models were applied to evaluate allele-dose effects. Multivariable logistic regression was performed to identify independent predictors of SRR. Predictive performance of clinical and combined clinical-genetic models was assessed using ROC curve analysis.
FSHB and FSHR genes polymorphisms were associated with variations in serum FSH concentrations, confirming a modulatory role of the FSH-related genes. In additive modeling, the FSHR c.29 G > A polymorphism emerged as an independent predictor of SRR (adjusted OR: 0.29; 95% CI, 0.09-0.97), whereas FSHB c.211 G > T showed a nonsignificant trend. The inclusion of genetic variants modestly improved predictive accuracy compared with clinical variables alone, as demonstrated by ROC analysis.
Genetic variants within the genes involved in FSH action might contribute incremental information for the prediction of sperm retrieval in patients with KS. While the overall predictive gain remains moderate, additive genetic modeling highlights a potential allele-dose effect of FSHR c.29 G > A on reproductive outcome, supporting a role for integrated clinical-genetic assessment in this population, although external validation remains required.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Garolla A et al., 2015·Human reproduction (Oxford, England)
Is there a difference between molecular karyotype of single sperm selected by high-magnification microscopy from infertile patients with testicular damage and from proven fertile controls?
The molecular karyotype of single sperm from patients with testiculopathy had a significantly higher percentage of chromosomal alterations than fertile controls.
Infertile patients with testicular impairment have many sperm with aneuploidies and/or increased structural chromosome alterations. In these patients, sperm use by ICSI has poor outcome and raises concerns about the possible impact on pregnancy loss and transmission of genes abnormalities in offspring. High-magnification microscopy has been recently introduced to select morphologically better sperm aimed at improving ICSI outcome. However, there are no studies evaluating the molecular karyotype of sperm selected by this method.
STUDY DESIGN, SIZE, Three consecutive infertile patients with oligozoospermia due to testicular damage and three age-matched proven fertile men attending a tertiary care center, were enrolled in the study from September to November 2014. Inclusion criteria of patients were age ≥30 ≤35 years, at least 2 years of infertility, oligozoospermia (sperm count below 10 million), reduced testicular volumes high FSH plasma levels and absence of altered karyotype, Y chromosome microdeletions, cystic fibrosis transmembrane conductance regulator gene mutations, sperm infections, cigarette smoking, varicocele, obesity.
PARTICIPANTS/MATERIALS, SETTING, Participants were evaluated for sperm parameters, sex hormones and testicular color-doppler ultrasound. From each semen sample, 20 sperm with large vacuoles (LVs), 20 with small vacuoles (SVs) and 20 with no vacuoles (NVs) were retrieved individually by a micromanipulator system. Each cell was further analyzed by whole genome amplification and array comparative genomic hybridization (aCGH).
MAIN The aCGH allowed us to detect chromosomal aneuploidies, unbalanced translocations and complex abnormalities. Sperm selected from infertile patients showed a higher percentage of abnormal molecular karyotypes than controls (19.4 versus 7.7%, respectively, P < 0.001). In particular, sperm with LV and SV showed 38.3 and 20.0% abnormal karyotype in infertile men versus 18.3 and 5.0% in controls, respectively (both P < 0.01). Complex abnormalities were found only in the LV category. An abnormal karyotype was never found in NV sperm from both patients and controls.
LIMITATIONS The main limitation of this study is the low number of included subjects. Moreover, a time of writing we have no data regarding the ICSI outcome using LV, SV or NV sperm. This is the first study evaluating the molecular karyotype of single sperm selected by high-magnification microscopy and further confirmation of the data is needed.
Our data showed that sperm from infertile patients with testicular impairment have a higher percentage of abnormal molecular karyotypes than sperm from fertile controls. Therefore, if confirmed, our data suggest that the use of individually retrieved NV sperm may improve ICSI outcome in infertile men with testicular damage.
Male Fertility › Male Reproductive Surgery › Sperm Retrieval Procedures · Assisted Reproduction › Outcomes and Effectiveness › Outcomes by Diagnosis · Genetics and Immunology › Reproductive Genetics › Chromosomal Abnormalities
Alessandro Pizzocaro, Fiore Pelliccione, Linda Vignozzi, Emmanuele A Jannini, Andrea Lenzi, Daniela Pasquali
A Pizzocaro, F Pelliccione, L Vignozzi, E Jannini, A Lenzi, D Pasquali
PMID 28379559 28379559 DOI 10.1093/humupd/dmx008 10.1093/humupd/dmx008 Corona et al. 2017, Corona 2017
