Complete deletions of the AZFc region in distal Yq are the most frequent molecular genetic cause of severe male infertility. They are caused by intrachromosomal homologous recombination between amplicons--large, nearly identical repeats--and are found in 5-10% of cases of azoospermia and severe oligozoospermia. Homologous recombination may also generate different partial deletions of AZFc, but their contribution to spermatogenic impairment has not been confirmed.
Methods
In this study we analysed the prevalence and characteristics of different partial AZFc deletions and their association with spermatogenic failure. We studied 337 infertile men with different spermatogenic impairment and 263 normozoospermic fertile men using AZFc specific sequence tagged site markers and DAZ specific single nucleotide variants.
Results
We identified 18 cases of partial AZFc deletions in the infertile group (5.3%) and one case in the control group (0.4%). Seventeen deletions had the "gr/gr" pattern, one the "b2/b3" pattern, and one represented a novel deletion with breakpoints in b3 and b4 amplicons. Partial AZFc deletions were associated with different spermatogenic phenotypes ranging from complete azoospermia to only moderate oligozoospermia.
Conclusions
Together with published data, our analysis of DAZ gene copy suggested that the contribution of the different deletions to male infertility varies: only partial AZFc deletions removing DAZ1/DAZ2 seem to be associated with spermatogenic impairment, whereas those removing DAZ3/DAZ4 may have no or little effect on fertility. These data show that, beside complete AZFc deletions, specific partial deletions represent a risk factor for male infertility, even if with different effect on spermatogenesis.
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
Moro E et al., 2000·The Journal of clinical endocrinology and metabolism
Deletions in distal Yq interval 6 represent the cause of 10-15% of idiopathic severe male infertility and map to a region defined AZFc (azoospermia factor c). The testis-specific gene DAZ is considered a major AZFc candidate, and its deletion has been associated with a severe disruption in spermatogenesis. However, DAZ is actually a multicopy gene family consisting of seven clustered copies spanning about 1 megabase. Only deletions removing the entire DAZ gene cluster together with other genes have been reported in infertile males. Because no case of spermatogenic failure has been traced to intragenic deletions, point mutations, or even deletions not involving all the DAZ copies, the definitive proof for a requirement of DAZ for spermatogenesis is still debatable. Here we report the first case of a partial deletion of the DAZ cluster removing all but one of the copies. This deletion is present in a patient affected with severe oligozoospermia who had a testicular phenotype characterized by a great quantitative reduction of germ cells (severe hypospermatogenesis). The absence of this deletion in the fertile brother of the patient suggests that this de novo mutation indeed caused the spermatogenic failure.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Three different spermatogenesis loci have been mapped on the Y chromosome and named "azoospermia factors" (AZFa, b, and c). Deletions in these regions remove one or more of the candidate genes (DAZ, RBMY, USP9Y, and DBY) and cause severe testiculopathy leading to male infertility. We have reviewed the literature and the most recent advances in Y chromosome mapping, focusing our attention on the correlation between Y chromosome microdeletions and alterations of spermatogenesis. More than 4,800 infertile patients were screened for Y microdeletions and published. Such deletions determine azoospermia more frequently than severe oligozoospermia and involve especially the AZFc region including the DAZ gene family. Overall, the prevalence of Y chromosome microdeletions is 4% in oligozoospermic patients, 14% in idiopathic severely oligozoospermic men, 11% in azoospermic men, and 18% in idiopathic azoospermic subjects. Patient selection criteria appear to substantially influence the prevalence of microdeletions. No clear correlation exists between the size and localization of the deletions and the testicular phenotype. However, it is clear that larger deletions are associated with the most severe testicular damage. Patients with Y chromosome deletions frequently have sperm either in the ejaculate or within the testis and are therefore suitable candidates for assisted reproduction techniques. This possibility raises a number of medical and ethical concerns, since the use of spermatozoa carrying Y chromosome deletions may produce pregnancies, but in such cases the genetic anomaly will invariably be passed on to male offspring.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Ferlin A et al., 2002·Journal of endocrinological investigation
The deleted-in-azoospermia (DAZ) gene family constitutes the major candidate for the AZFc (azoospermia factor c) phenotype of male infertility, being deleted in about 10% of azoospermic and severely oligozoospermic subjects. Four DAZ genes are arranged in two clusters in AZFc, and standard analysis by PCR cannot distinguish among the different copies. Therefore only deletions of the entire gene cluster can be identified. We developed a PCR amplification-restriction digestion assay able to distinguish from DAZ genes for single nucleotide variants. Then we applied this approach to screen a group of idiopathic infertile men in which the DAZ genes presence was previously assessed by standard PCR analysis. Two patients out of 25 showed deletion of two copies of DAZ (DAZI and 2), suggesting that this mutation was actually the cause of spermatogenic damage. This preliminary screening demonstrates that deletions of copies of DAZ genes may be often found in severely infertile men and it strengthens the role of this gene family in spermatogenesis. Furthermore, this simple method, being able to distinguish among the different DAZ copies, could be used to screen a larger number of patients and to perform a more accurate diagnosis.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Graziani A et al., 2024·Human reproduction (Oxford, England)
Genetic causes account for 10-15% of male factor infertility, making the genetic investigation an essential and useful tool, mainly in azoospermic and severely oligozoospermic men. In these patients, the most frequent findings are chromosomal abnormalities and Y chromosome long arm microdeletions, which cause a primary severe spermatogenic impairment with classically increased levels of FSH. On the other hand, polymorphisms in the FSH receptor (FSHR) and FSH beta chain (FSHB) genes have been associated with different FSH plasma levels, due to variations in the receptor sensitivity (FSHR) or in the production of FSH from the pituitary gland (FSHB). Here, we describe an unusual patient with a combined genetic alteration (classic AZFc deletion of the Y chromosome and TT homozygosity for the -211G>T polymorphism in the FSHB gene (rs10835638)), presenting with cryptozoospermia, severe hypospermatogenesis, and normal LH and testosterone plasma concentrations, but low FSH levels. The patient partially benefitted from treatment with FSH (150 IU three times/week for 6 months) which allowed him to cryopreserve enough motile spermatozoa to be used for intracytoplasmic sperm injection. According to our knowledge, this is the first report of an infertile man with AZFc microdeletion with low FSH plasma concentrations related to homozygosity for the -211G>T polymorphism in the FSHB gene.
Male Fertility › Male Endocrine and Genetic Factors › Genetic Causes of Male Infertility · Genetics and Immunology › Reproductive Genetics › Chromosomal Abnormalities
PMID 15744033 15744033 DOI 10.1136/jmg.2004.025833 10.1136/jmg.2004.025833 Ferlin et al. 2005, Ferlin 2005
00240q980