Abstract
Background
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.
Objective
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.
Materials and Methods
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".
Results
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.
Discussion and Conclusions
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.
By this author
Semen Analysis · Sperm Function Testing
Preimplantation genetic testing for male factor infertility: lights and shadows
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.
Male Factor Causes · Hormonal Causes
Pathophysiology-Based Classification of Male Infertility: Evidence from an 800-patient Prospective Cohort
Grande G et al., 2026 · The Journal of clinical endocrinology and metabolism · Free to read
Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted management. To phenotypically define MFI and develop a pathophysiology-based classification aimed at reducing idiopathic infertility following comprehensive evaluation. Prospective monocentric cohort study conducted at a tertiary referral academic centre. Eight hundred male partners of infertile couples evaluated between October 2024 and January 2026 after exclusion of isolated female factor infertility. Prevalence of MFI categories, hormonal patterns across phenotypes, and proportion of idiopathic infertility after comprehensive work-up. All patients underwent standardized clinical evaluation, hormonal assessment (total testosterone, FSH, LH), testicular ultrasound, and complete semen analysis. Microbiological testing, transrectal ultrasound, and genetic analyses were performed according to guidelines. Primary spermatogenic failure was the most prevalent category (56.0%), followed by infection/inflammation (22.4%) and hypogonadotropic hypogonadism (8.5%). Idiopathic infertility was identified in only 5.3% of cases. Distinct endocrine profiles were observed, with high-FSH spermatogenic failure representing the dominant phenotype. Comprehensive phenotyping markedly reduces the proportion of patients classified as having idiopathic infertility and identifies clinically relevant subgroups. This prospective study provides validation of a pathophysiology-based classification and supports a shift toward endocrine-integrated diagnostic strategies in male infertility, with potential implications for targeted management.
Semen Analysis · Sperm Function Testing
Beyond semen analysis: in men with normal semen parameters telomere attrition and oxidative imbalance distinguish those fertile from those with infertility
Rocca MS et al., 2026 · Journal of translational medicine · Free to read
Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from infertile men, i.e. partners of couples with idiopathic infertility. Oxidative stress, mitochondrial dysfunction, sperm telomere shortening, and DNA fragmentation have been proposed as contributors to impaired male fertility. However, these biomarkers have not been evaluated as a whole in subjects with normal semen parameters, partners of fertile and infertile couples. To characterise a multidimensional panel of sperm biomarkers-including sperm telomere length (STL), mitochondrial DNA copy number (mtDNAcn), reactive oxygen species (ROS), lipid peroxidation (LP), sperm chromatin dispersion (SCD), and respiratory control ratio (RCR)-and to identify whether these parameters might discriminate, in men with normal semen parameters, infertile men from fertile controls. A total of 150 men with semen parameters within the normal ranges were enrolled: 47 male partners of couples with idiopathic infertility and 103 fertile controls. STL and mtDNAcn were quantified by qPCR; ROS were assessed using OxiSperm®II with semiquantitative imaging; LP was measured spectrophotometrically in seminal plasma; SCD was used to determine DNA fragmentation; and mitochondrial function was evaluated by oxygen consumption and RCR. Correlations between biomarkers and semen parameters were analysed using Pearson or Spearman coefficients, and intergroup comparisons were adjusted for age. Semen parameters did not differ significantly between male partners of fertile and infertile couples. compared to men of fertile couples, men of infertile couples exhibited significantly shorter STL (0.57 ± 0.59 vs 1.21 ± 1.13, p_adj = 0.001) and higher oxidative stress, with both ROS (8300.9 ± 4214.8 vs 6555.3 ± 3394.3, p_adj = 0.027) and LP (88.33 ± 55.50 vs 40.29 ± 46.98, p_adj < 0.001) markedly elevated. mtDNAcn, SCD, and RCR showed no difference between the groups. Across the entire cohort, STL correlated negatively with ROS and LP and positively with RCR. ROS correlated negatively with total sperm count, motility and RCR, and positively with LP. LP displayed the strongest pattern of associations, correlating negatively with concentration, total count, motility, STL and RCR, and positively with age and volume. Among men with normal semen analysis, partners of couples with idiopathic infertility exhibit a distinct sperm molecular profile characterised by telomere shortening and oxidative imbalance. STL, ROS and LP emerged as age-independent biomarkers associated with infertility status and showed promising discriminatory ability in this cohort, supporting their integration as second-level tests to complement routine semen analysis in cases of normozoospermia.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Impact of FSHB and FSHR Genes Polymorphisms on Hormonal Profile and Sperm Retrieval Outcome in Men With Klinefelter Syndrome: A Clinical-Genetic Predictive Study
Graziani A et al., 2026 · Andrology · Free to read
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.
Related research
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
The Klinefelter Puberty
Milardi D et al., 2020 · Klinefelter's Syndrome
Klinefelter syndrome (KS) is a common genetic disorder characterized by an additional X chromosome in males. A deficient androgen production and a varied observed response of end-organs to testosterone can lead to delayed progression of puberty with reduction in muscle development and facial/body hair, osteoporosis, and gynecomastia. Medical management during puberty focuses on the preservation of fertility and testosterone replacement treatment (TRT) to reduce the current or future consequences of testicular fibrosis. However, more research is needed to establish the need and conditions for TRT in adolescence, as well as the opportunity and timing for sperm recovery in adolescents and young boys with KS. Furthermore, screening for associated diseases such as metabolic syndrome, osteoporosis, and malignancies should be guaranteed during this lifetime. Preventive care should be provided by diagnosis, ideally through a multidisciplinary approach.
Guidelines by Clinical Area · Bone and Endocrine Guidelines
Recommendations for diagnosis and treatment of the aging male with Klinefelter syndrome
Zitzmann M et al., 2025 · The aging male : the official journal of the International Society for the Study of the Aging Male · Free to read
This is the inaugural recommendation for the management of the Aging Male with Klinefelter Syndrome (KS), a demographic characterized by primary hypogonadism in the presence of one or more supernumerary X-chromosomes with irregular gene-inactivation, and metabolic dysregulation, contributing a component of functional hypogonadism as aging in these men progresses. The unique constellation of symptoms spanning multiple organ systems and health domains necessitates specialized diagnostic and therapeutic strategies. Neglecting the specific needs of this population can precipitate a considerable decline in quality of life and overall health outcomes. Our recommendations advocate for a multidisciplinary approach involving endocrinologists, urologists, geneticists, mental health professionals, and other specialists, to address the complex interplay of hormonal imbalances, metabolic disorders, cardiovascular risk factors including arrhythmia, bone health concerns, psychological and sexual challenges, ophthalmological problems, and dental issues. By providing a structured framework for comprehensive and individualized care, these recommendations aim to bridge existing healthcare gaps, optimize well-being, and enhance the overall quality of life for aging men with KS.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology
Zitzmann M et al., 2021 · Andrology · Free to read
Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. To create the first European Academy of Andrology (EAA) guidelines on KS. An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone-related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts.
Hormonal Agents · Androgens and DHEA
The Klinefelter syndrome: current management and research challenges
Nieschlag E et al., 2016 · Andrology
Following the 1st International Workshop on the Klinefelter Syndrome in 2010 (Juul et al., 2011), the 2nd IWKS took place in Münster, Germany from March 10 to 12, 2016 and was organized by the Centre of Reproductive Medicine and Andrology of the University of Münster. During the program, talks were presented by leading researchers in the field followed by lively discussions among the 120 participants. The talks comprehensively covered basic and clinical aspects of the syndrome. The basic aspects included the mechanisms of X chromosome inactivation (Joost Gribnau, Christine Disteche), sex chromosome evolution in the primate lineage (Gabriel Marais), epigenetics (Joana Viana), gene expression studies (Liborio Stuppia), and animal models (Art Arnold, Armin Raznahan, Joachim Wistuba). Among the clinical aspects, current views on early/prenatal diagnosis (Frank Tüttelmann) and transitional care (Niels E. Skakkebæk, Alan Rogol) were reviewed. A large part of the workshop was devoted to comorbidities – with focus on cardiovascular and metabolic problems (Michael Zitzmann, Anders Bojesen) as well as osteoporosis (Alberto Ferlin). Neuropsychological, behavioral, and socioeconomic aspects were discussed (Hanna Swaab, Anne Skakkebæk, Nicole Tartaglia). Divergent experiences and opinions on fertility preservation and optimal time for TESE were presented (Sabine Kliesch, Hervé Lejeune). Following new findings on testicular steroidogenesis (Manuela Simoni), testosterone replacement in infants and young children (Carole Samango-Sprouse) and age-specific recommendations for management of patients with Klinefelter Syndrome (KS) met with great interest (Anders Juul). Differences and similarities between KS and Turner syndrome provided further insights into disorders of sex chromosome aneuploidies (Claus H. Gravholt). Finally, results of the 'dsd-LIFE study' on quality of life, satisfaction with care and needs of adolescents and men with KS (Birgit Köhler) and the European COST Initiative on DSD including KS (Olaf Hiort) were presented (for details of the program see www.klinefelter2016.de). The purpose of the concluding round table was to discuss – based on the presentations and interactions of this workshop – the shortcomings of current care of patients with KS and to indicate future directions for patient management and research. As an introduction, tribute was paid to Harry F. Klinefelter (1912–1990), who first described this syndrome in 1942 (Klinefelter et al., 1942). Of the 120 workshop participants, only Alan Rogol and Eberhard Nieschlag had met Harry Klinefelter in person, the former as one of his medical teachers at John Hopkins in Baltimore and the latter at an International Klinefelter Symposium in Murnau in the Bavarian Alps in 1983 (Bandmann et al., 1984). The discussion was opened by arguments for and against neonatal screening for KS as this question had come up repeatedly during the workshop. Alan Rogol gave the reasons for screening all male newborns for 47,XXY (and perhaps all children for sex chromosome aneuploidy): primarily in anticipation of services required in childhood, such as early treatment of deficits encountered in speech, behavior/regulation of emotion, physical findings, delayed childhood milestones. Furthermore, for information of parents, doctors, and health care practitioners as well as school and pre-school personnel (as much as parents wish, for there is a risk of stigmatization). An overarching service/education that pediatricians have to offer is anticipatory guidance, and newborn screening would allow pediatricians to provide this guidance to families concerned with KS. However, based on his experience in Denmark, Claus H. Gravholt felt that it was premature to screen large populations for KS, as we do not yet have evidence that the different treatment options that we can provide are efficient and reduce morbidity, mortality, and improve outcome. There is no proof yet that early diagnosis and treatment [truncated]
A Di Mambro
PMID 42299463 42299463 DOI 10.1111/andr.70277 10.1111/andr.70277 Graziani et al. 2026, Graziani 2026