Male Fertility · Male Factor Causes
Garolla A, Pizzol D, Bertoldo A, Ghezzi M, Carraro U, Ferlin A, Foresta C
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Testicular cancer represents the more frequent solid tumor affecting males aged 15-35 years. In the last decades, its incidence showed a progressive increased probably due to genetic and environmental factors. Despite exposure to some viruses such as HIV, HCV, EBV, and HPV is frequently related to cancer development, there are no studies aimed to evaluate the possible implication of viral infections in the pathogenesis of testicular cancer. In this study, we analyzed sperm parameters and prevalence of HPV on sperm in 155 testicular cancer patients at diagnosis (T-1), after orchiectomy (T0) and after 12 months from surgery or from the end of adjuvant treatments (T12). All patients showed a significantly higher prevalence of semen infection than controls (9.5% and 2.4% respectively,) and altered sperm parameters both at T-1 and T0. Considering sperm parameters, at T-1 we observed a reduction of progressive motility, and after orchiectomy patients showed a reduction of sperm concentration and count and a further worsening of motility. Thereafter, patients were assigned to three groups on the basis of medical option after surgery: S = surveillance, R = radiotherapy, and C = chemotherapy +/- radiotherapy. At T12, untreated patients had an improvement of sperm parameters while R group and even more C group had a strong decrease of sperm number (p < 0.01 both vs. T0 and S group). Moreover, patients who received radio and/or chemotherapy had a very high prevalence of HPV semen infection (S = 7.7%, R = 30.8%, and C = 61.5%). In conclusion, patients with testicular cancer had frequently altered sperm parameters and higher prevalence of HPV semen infection that were worsened after radio and chemotherapy. Because HPV infection is a risk factor for cancer development and it may further reduce fertility, we suggest screening for HPV in testicular cancer patients at diagnosis and particularly after adjuvant treatments.
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.
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.
Foresta C et al., 2011 · PloS one · Free full text on PubMed Central
Human papillomaviruses (HPVs) are agents of the most common sexually transmitted diseases in females and males. Precise data about the presence, mechanism of infection and clinical significance of HPV in the male reproductive tract and especially in sperm are not available. Here we show that HPV can infect human sperm, it localizes at the equatorial region of sperm head through interaction between the HPV capsid protein L1 and syndecan-1. Sperm transfected with HPV E6/E7 genes and sperm exposed to HPV L1 capsid protein are capable to penetrate the oocyte and transfer the virus into oocytes, in which viral genes are then activated and transcribed. These data show that sperm might function as vectors for HPV transfer into the oocytes, and open new perspectives on the role of HPV infection in males and are particularly intriguing in relation to assisted reproduction techniques.
Lifshitz K et al., 2026 · International urology and nephrology · Free to read
Paternity rates among testicular cancer survivors are reduced. The patient journey, from fertility preservation at diagnosis to attempted paternity or use of assisted reproductive technologies (ART), contains two key gaps in the literature. While baseline semen impairment is well recognized, the relationship between disease stage, tumor pathology, and semen quality remains inconsistent. In addition, prior studies have largely excluded sex-cord stromal tumors, lacked healthy comparators, and rarely performed pathology-specific analyses within the same clinical stage. Reported paternity rates vary widely (6-21%), yet real-world data on ART utilization and live-birth outcomes remain limited. We conducted a retrospective cohort study (2017-2023) at a single tertiary academic referral center within a healthcare system that provided full coverage for sperm cryopreservation for 5 years and ART for up to 2 live births. Primary outcomes included baseline semen parameters by tumor histology and clinical stage, pathology-specific comparisons within each stage, and post-treatment utilization of cryopreserved sperm. Secondary outcomes were ART pregnancy and live-birth rates. The semen parameters were compared with those of healthy sperm donor candidates. The cohort included 126 men (mean age 36.6 ± 10.9 years; 83 seminoma, 35 non-seminoma, 8 sex-cord stromal tumors). Compared with 100 healthy donor candidates, testicular cancer patients demonstrated significantly impaired baseline semen quality across all parameters except volume (all p ≤ 0.01). Post-thaw semen quality was further reduced, with lower motility rates (17.5% vs 44.1%) and total motile counts (1.1 vs 7.8 million), highlighting greater motility and total motile count loss following cryopreservation. Sex-cord stromal tumors exhibited the poorest semen parameters. Semen quality did not differ by stage overall; pathology-specific differences were observed only in stage II disease, favoring non-seminoma tumors (p ≤ 0.05). Overall, 69% (n = 91) elected sperm cryopreservation. Among those, the median number of vials initially frozen was 15 (IQR 10-18), with a mean of 11.6 ± 4.3 vials per patient (range 1-18). During a median follow-up of 5.3 years (IQR: 3.9-6.8), only 8% (n = 7) used their vials for ART, undergoing a median (IQR) of 2.5 (1-4) cycles per couple (15 cycles recorded among 6 of 7 couples; cycle count missing for one couple), resulting in 12 pregnancies and an overall live-birth rate of 67%: 2/2, 100%, 6/10, 60%. Testicular cancer significantly impairs semen quality, with important variation by tumor pathology rather than stage. These findings underscore the need for accurate counseling: fertility preservation often enables future use primarily through IVF and supports banking multiple vials to mitigate freeze-thaw losses.
Lackamp N et al., 2021 · Frontiers in oncology · Free full text on PubMed Central
Progress in oncological treatment has led to an improved long-term survival of young male cancer patients over the last decades. However, standard cancer treatments frequently implicate fertility-damaging potential. Cryopreservation of sperm is the current standard option to preserve patient's fertility after treatment, yet long-term data on usage and reproductive experiences is still limited. Natural fertility after treatment and especially in relation to the type of treatment has been poorly analyzed so far. Therefore, we performed a retrospective survey including male patients with an indication for gonadotoxic treatment who cryopreserved reproductive material at our institution between 1994 and 2017. Study questionnaires regarding treatment, material usage, and reproductive outcomes were sent to eligible patients. Additionally, semen analyses of study participants from the time of cryopreservation were evaluated. A total of 99 patients were included in the study. Respondents' median age was 38.0 years. Most frequent diagnoses were testicular cancer (29.3%) and lymphoma (26.3%). A further 8.1% suffered from autoimmune diseases. Testicular cancer patients had a significantly lower pre-treatment median sperm concentration (18.0 million/ml) compared to non-testicular cancer patients (54.2 million/ml). Until November 2020, the determined sperm usage and cumulative live-birth rate per couple were 17.2% and 58.8%, respectively. Most sperm users received treatments with high (40.0%) or intermediate (33.3%) gonadotoxic potential. 20.7% of all patients reported to had fathered at least one naturally conceived child after treatment, this being the case especially if they had been treated with less or potentially gonadotoxic therapies. In conclusion, our findings emphasize the importance of sperm cryopreservation in the context of male fertility preservation. Furthermore, they indicate that the gonadotoxic potential of patients' treatments could represent a predictive factor for sperm usage.
Nedelcu S et al., 2024 · Hum Reprod Open · Free full text on PubMed Central
Can semen parameters predict long-term health outcomes in men? There is a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration. Male infertility has been long associated with a higher mortality risk and possibly higher chance of developing comorbidities but there has been less focus on semen analysis as a potential predictive factor. We searched PubMed/MEDLINE, EMBASE, and EBM databases from inception to December 2023. MESH term strategy: heading 1 ('OR', semen analysis, sperm count, sperm parameter*, male infertility, azoospermia, aspermia, oligospermia, teratozoospermia, asthenozoospermia) 'AND' heading 2 ('OR', morbidity, mortality, diabetes, cancer, cardiovascular, death, hypertension, stroke, long-term health). We included all studies that analyzed the risk of mortality and/or future development of comorbidities in men with at least one semen analysis. Case series and reviews were excluded. A narrative synthesis was done for all studies and meta-analysis where possible. Odds ratio (ORs) (95% CI, P-value) were calculated for all men with one suboptimal semen parameter and associated with the risk of a particular outcome. The risk of bias was assessed with QUADAS-2. MAIN Twenty-one studies were finally included. There was either a high or unclear risk of bias in all studies. The results only allowed for meta-analysis on categories of sperm concentration. We found a 2-fold increase in mortality risk in azoospermic men compared to oligospermic (OR 1.96, 95% CI: 1.29-2.96) and normozoospermic (OR 2.00, 95% CI: 1.23-3.25) groups, but not in oligospermic compared to normozoospermic (OR 1.04, 95% CI: 0.52-2.09). There was no difference in risk of cardiovascular disease in any of the sperm concentration groups (azoospermic-oligospermic OR 0.94, 95% CI: 0.74-1.20, azoospermic-normozoospermic OR 1.11, 95% CI: 0.71-1.75, and oligospermic-normozoospermic OR 1.12, 95% CI: 0.80-1.55). OR for diabetes in azoospermic men was higher only compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01). The risk of all-site cancer was higher in azoospermic men compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01) and normozoospermic (OR 2.18, 95% CI: 1.20-3.96). Only azoospermic men might be at higher risk of testicular cancer when compared to men with normal sperm concentration (OR 1.80, 95% CI: 1.12-2.89). LIMITATIONS Although our pooled analysis shows an increased risk of mortality and all-site cancer risk in azoospermic men, the results show a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration. Given the limited available data, the nature of the studies, and the high risk of bias, the results should be interpreted with caution. There is not enough data to confirm the usability of semen analysis as a predictor of poor long-term health in men, especially within the general population. No funding was obtained for this study. A.M. has received funding from Merck Serono, Ferring, Gedeon Richter, Pharmasure, and Cook Medical to attend medical conferences; has been a participant in an advisory board for Ferring; and has given an invited lecture for a Merck Serono advisory board. S.N. has received funding for medical conference attendance from Ferring and Cook Medical. PROSPERO No. CRD42024507563.