Genetics and Immunology · Reproductive Genetics
Foresta C, Moro E, Ferlin A
Y chromosome microdeletions represent the most frequent genetic alteration in azoospermic and severely oligozoospermic men, and screening for microdeletions in AZFa, b and c are routinely performed in the major andrology and infertility centres. Since patients with Y microdeletions often require intracytoplasmic sperm injection (ICSI), the question of whether the type of the microdeletion present could have prognostic value for the presence of spermatozoa in the ejaculate or in the testes [by testicular sperm extraction (TESE)] is an interesting one. The review of the literature on this topic showed that there is still no clear genotype--phenotype relationship, i.e. similar testicular alterations may be caused by different types of microdeletions, and apparently identical microdeletions may be associated with diverse tubular damage. Even in azoospermic men, the localization of the microdeletion cannot be used as a valid prognostic parameter before TESE--ICSI to identify patients with spermatozoa in their testes. The only finding with absolute negative prognostic value is the presence of complete AZFa--c deletions, which are invariably associated with an absence of spermatozoa. Microdeletions in AZFa or AZFb seem to have promising prognostic value, but more data and gene-specific deletions have to be provided to draw clear conclusions. The absence of a clear genotype--phenotype relationship, and therefore of a prognostic value of Y deletion analysis, is probably due to the current methods used for the screening of the microdeletions. In fact, to date most centres do not use gene-specific markers but instead use anonymous primers that contribute little information to the pathogenic role of the microdeletions.
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.
Graziani A et al., 2026 · Andrology · Free to read
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.
De Toni L et al., 2026 · Journal of endocrinological investigation · Free full text on PubMed Central
Varicocele is a recognized male factor of infertility. Surgical/microsurgical correction represents a therapeutical option to improve fertility outcomes but predictive parameters for the identification who can actually benefit from varicocele correction are under investigated. Here we aimed to identify baseline predictors of semen outcome improvement after varicocele treatment by scleroembolization approach. 85 patients receiving varicocele treatment by anterograde scleroembolization (ASE, N = 42) or retrograde scleroembolization (RSE, N = 43) were retrospectively recruited. Basal and 6-months follow-up evaluation of semen, hormonal and ultrasound parameters (US) were performed to address the respective effect of varicocele treatment. In addition, basal parameters were assessed as clinical outcome predictors. Varicocele grade reduction was observed in more than 90% of patients (P < 0.001). Compared to basal, significant increase of sperm concentration (10.0 ± 9.2 × 106cells/mL vs. 23.4 ± 26.9 × 106cells/mL; P < 0.001), total sperm count (TSC 39.0 ± 54.5 × 106cells vs. 70.3 ± 90.6 × 106cells, P < 0.001) and total motile sperm count (TMS, 9.8 ± 12.8 × 106cells vs. 36.7 ± 58.1 × 106cells, P < 0.001), was observed, with no differences between RSE or ASE. All US parameters were also improved (all P < 0.001). Logistic regression analysis of basal semen and ultrasound parameters showed that basal sperm motility and left testis-mean transit time (L-MTT) were associated with TSC and TMS doubling at follow-up. However, Receiver Operating Characteristic curve analysis showed that only basal L-MTT basal sperm was consistently associated with TSC and TMS doubling at follow-up (respectively: AUC = 0.834, CI: 0.747-0.921 and AUC = 0.805, CI: 0.708-0.901; both P < 0.001). Baseline sperm count and US parameters represent useful clinical descriptors to address those subjects eligible for varicocele correction.
Foresta C et al., 1999 · Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna
We investigated the possible role of Y chromosome microdeletions in regions previously shown to be important for male germ cell development in unilateral ex-cryptorchid subjects manifesting important bilateral testiculopathy, in order to clarify whether cryptorchidism could be the expression of an intrinsic congenital testicular abnormality. Microdeletion analysis of the Y chromosome long arm was performed by polymerase chain reaction and confirmed by Southern blot in 40 selected unilateral ex-cryptorchid patients with azoospermia or severe oligozoospermia sustained by severe bilateral testiculopathy (Sertoli cell-only syndrome and severe hypospermatogenesis, respectively), 20 unilateral ex-cryptorchid men with moderate oligozoospermia and normal function of the descended testis, 110 patients affected by severe idiopathic primary testiculopathies, 20 patients affected by moderate idiopathic testiculopathy and, as controls, 50 patients affected by known causes of testiculopathy and 50 fertile controls. Eleven out of the 40 (27.5%) unilateral ex-cryptorchid patients affected by bilateral testiculopathy and 28 out of 110 (25.4%) patients affected by severe idiopathic primary testiculopathy showed microdeletions in the Y chromosome long arm, while all other subjects were normal. Male relatives of patients with deletions were also normal. Microdeletions were distributed in different regions of the Y chromosome long arm, including known regions involved in spermatogenesis (DAZ and RBM genes, AZFa, b and c regions) and other still poorly defined loci. No difference in localization of deletions was evident between ex-cryptorchid and idiopathic patients. Microdeletions in the Y chromosome may be responsible for bilateral severe testicular damage: the clinical consequence, other than idiopathic azoospermia and severe oligozoospermia, may also be unilateral cryptorchidism, probably due to altered testicular responses to mechanisms regulating testicular descent.
Ferlin A et al., 1999 · Human reproduction (Oxford, England)
Microdeletions in Yq11 overlapping three distinct 'azoospermia factors' (AZFa-c) represent the aetiological factor of 10-15% of idiopathic azoospermia and severe oligozoospermia, with higher prevalence in more severe testiculopathies, such as Sertoli cell-only syndrome. Using a PCR-based screening, we analysed Yq microdeletions in 180 infertile patients affected by idiopathic Sertoli cell-only syndrome and different degrees of hypospermatogenesis, compared with 50 patients with known causes of testicular alteration, 30 with obstructive azoospermia, and 100 normal fertile men. In idiopathic severe testiculopathies (Sertoli cell-only syndrome and severe hypospermatogenesis), a high prevalence of microdeletions (34.5% and 24.7% respectively) was found, while milder forms were not associated with Yq alteration. No deletions were found in testiculopathies of known aetiology, obstructive azoospermia, normal fertile men and male relatives of patients with deletions. Deletions in the AZFc region involving the DAZ gene were the most frequent finding and they were more often observed in severe hypospermatogenesis than in Sertoli cell-only syndrome, suggesting that deletions of this region are not sufficient to cause complete loss of the spermatogenic line. Deletions in AZFb involving the RBM gene were less frequently detected and there was no correlation with testicular phenotype, with an apparent minor role for such gene in spermatogenesis. The DFFRY gene was absent in a fraction of patients, making it a candidate AZFa gene. Our data suggest that larger deletions involving more than one AZF-candidate gene are associated with a more severe testicular phenotype.
Foresta C et al., 2001 · Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna
Microdeletions of the Y chromosome represent the most frequent cause of male infertility, being responsible for 10-15% of cases of azoospermia or severe oligozoospermia. Such mutations localize in one or more loci named azoospermia factor (AZF) a, b and c. Mutations more frequently involve the DAZ gene in AZFc, and could determine both azoospermia and severe oligozoospermia. It is therefore difficult to find a clear relationship between genotype and phenotype. DAZ is present in multiple copies in AZFc, and this causes the gene to be difficult to analyze. In fact, polymerase chain reaction, the principal technique utilized for detection of the deletions, cannot distinguish among the different copies of the gene. Furthermore, it is not clear if all the DAZ copies are expressed in the testis, and other genes, such as CDY1, map in AZFc; therefore their alteration may play a role in determining the phenotype. In this review we report the current knowledge on the function of the Y chromosome in human spermatogenesis. In particular we analyze some of our experimental studies on the role of the DAZ gene family. Expression studies allowed us to clarify that an altered expression of DAZ might cause infertility in patients with severe testiculopathies. Furthermore, we describe for the first time a deletion not involving all the DAZ copies in a patient with severe hypospermatogenesis and we clarify that CDY1 is not involved in the testicular damage observed in patients with deletions of DAZ. These studies elucidate the role of DAZ and have important clinical consequences in the diagnostic and therapeutic approach of the infertile patient, above all when he is a candidate for assisted reproduction techniques, due to the possibility of transmitting the genetic alteration to the offspring.
Foresta C et al., 1997 · The Journal of clinical endocrinology and metabolism
A genetic etiology has been recently proposed for some severe forms of idiopathic male infertility and a region of the Y chromosome long arm (Yq) defined AZF is thought to be critical for the regulation of spermatogenesis. To date, two genes, YRRM and DAZ, have been identified in AZF, but the actual relationship between genotype and phenotype related to AZF deletions is not well characterized. By means of a PCR strategy we typed Yq microdeletions in 16 azoospermic and 22 severely oligozoospermic subjects whose testicular cytological picture (assessed by fine needle aspiration) was that of Sertoli cell-only syndrome and severe hypospermatogenesis, respectively. Microdeletions in AZF were found in 37.5% of azoospermic men and in 22.7% of severely oligozoospermic men, suggesting that very frequently these genetic abnormalities determine a severe quantitative defect in spermatogenesis. Furthermore, DAZ and YRRM do not seem to be the sole genes regulating spermatogenesis, as deletions in these genes were observed in only 6 of the 11 deleted cases. No correlation between the spermatogenic defect and the type of Yq deletion exists. Intracytoplasmic sperm injection performed using spermatozoa of these Y-deleted patients will invariably pass this defect onto their male offspring. Screening for deletion within AZF or at least an informed consent should, therefore, be obtained in all idiopathic infertile male undergoing a program of intracytoplasmic sperm injection of a spermatozoon into the oocyte.
