Infertility is a prevalent issue affecting many couples during their reproductive years, with a significant number facing challenges in conceiving despite regular unprotected intercourse. Male factor infertility (MFI) contributes significantly to these cases, with a significant proportion of men lacking an identifiable etiology. As such, a thorough assessment of MFI has become increasingly vital for personalized management. This position paper from the Andrology team at IRCCS Ospedale San Raffaele emphasizes a comprehensive and individualized approach to MFI work-up, addressing the evolving challenges encountered in clinical practice. Our approach involves a thorough diagnostic work-up to identify the underlying causes of MFI, integrating insights from extensive literature review and our proprietary data. Our data demonstrates that an extensive diagnostic assessment allows us to identify at least one underlying cause of MFI in most infertile men. However, challenges persist in diagnosing less severe phenotypes with unclear etiology. We discuss the importance of individualized MFI work-up and its implications for developing rational therapeutic protocols. Lastly, this paper highlights the necessity for a personalized diagnostic assessment, addressing the daily clinical challenges and emphasizing tailored approaches to try to improve outcomes among couples seeking first medical help for infertility.

Infertility is a prevalent issue affecting many couples during their reproductive years, with a significant number facing challenges in conceiving despite regular unprotected intercourse. Male factor infertility (MFI) contributes significantly to these cases, with a significant proportion of men lacking an identifiable etiology. As such, a thorough assessment of MFI has become increasingly vital for personalized management. This position paper from the Andrology team at IRCCS Ospedale San Raffaele emphasizes a comprehensive and individualized approach to MFI work-up, addressing the evolving challenges encountered in clinical practice. Our approach involves a thorough diagnostic work-up to identify the underlying causes of MFI, integrating insights from extensive literature review and our proprietary data. Our data demonstrates that an extensive diagnostic assessment allows us to identify at least one underlying cause of MFI in most infertile men. However, challenges persist in diagnosing less severe phenotypes with unclear etiology. We discuss the importance of individualized MFI work-up and its implications for developing rational therapeutic protocols. Lastly, this paper highlights the necessity for a personalized diagnostic assessment, addressing the daily clinical challenges and emphasizing tailored approaches to try to improve outcomes among couples seeking first medical help for infertility.

Infertility is a prevalent issue affecting many couples during their reproductive years, with a significant number facing challenges in conceiving despite regular unprotected intercourse. Male factor infertility (MFI) contributes significantly to these cases, with a significant proportion of men lacking an identifiable etiology. As such, a thorough assessment of MFI has become increasingly vital for personalized management. This position paper from the Andrology team at IRCCS Ospedale San Raffaele emphasizes a comprehensive and individualized approach to MFI work-up, addressing the evolving challenges encountered in clinical practice. Our approach involves a thorough diagnostic work-up to identify the underlying causes of MFI, integrating insights from extensive literature review and our proprietary data. Our data demonstrates that an extensive diagnostic assessment allows us to identify at least one underlying cause of MFI in most infertile men. However, challenges persist in diagnosing less severe phenotypes with unclear etiology. We discuss the importance of individualized MFI work-up and its implications for developing rational therapeutic protocols. Lastly, this paper highlights the necessity for a personalized diagnostic assessment, addressing the daily clinical challenges and emphasizing tailored approaches to try to improve outcomes among couples seeking first medical help for infertility.

Infertility is a prevalent issue affecting many couples during their reproductive years, with a significant number facing challenges in conceiving despite regular unprotected intercourse. Male factor infertility (MFI) contributes significantly to these cases, with a significant proportion of men lacking an identifiable etiology. As such, a thorough assessment of MFI has become increasingly vital for personalized management. This position paper from the Andrology team at IRCCS Ospedale San Raffaele emphasizes a comprehensive and individualized approach to MFI work-up, addressing the evolving challenges encountered in clinical practice. Our approach involves a thorough diagnostic work-up to identify the underlying causes of MFI, integrating insights from extensive literature review and our proprietary data. Our data demonstrates that an extensive diagnostic assessment allows us to identify at least one underlying cause of MFI in most infertile men. However, challenges persist in diagnosing less severe phenotypes with unclear etiology. We discuss the importance of individualized MFI work-up and its implications for developing rational therapeutic protocols. Lastly, this paper highlights the necessity for a personalized diagnostic assessment, addressing the daily clinical challenges and emphasizing tailored approaches to try to improve outcomes among couples seeking first medical help for infertility.

Infertility is a prevalent issue affecting many couples during their reproductive years, with a significant number facing challenges in conceiving despite regular unprotected intercourse. Male factor infertility (MFI) contributes significantly to these cases, with a significant proportion of men lacking an identifiable etiology. As such, a thorough assessment of MFI has become increasingly vital for personalized management. This position paper from the Andrology team at IRCCS Ospedale San Raffaele emphasizes a comprehensive and individualized approach to MFI work-up, addressing the evolving challenges encountered in clinical practice. Our approach involves a thorough diagnostic work-up to identify the underlying causes of MFI, integrating insights from extensive literature review and our proprietary data. Our data demonstrates that an extensive diagnostic assessment allows us to identify at least one underlying cause of MFI in most infertile men. However, challenges persist in diagnosing less severe phenotypes with unclear etiology. We discuss the importance of individualized MFI work-up and its implications for developing rational therapeutic protocols. Lastly, this paper highlights the necessity for a personalized diagnostic assessment, addressing the daily clinical challenges and emphasizing tailored approaches to try to improve outcomes among couples seeking first medical help for infertility.

Purpose: To assess the relationship between clinical and semen characteristics and assisted reproductive technology (ART) outcomes with different birth weight (BW) categories in a cohort of infertile men. Materials and Methods: Data from 1,063 infertile men were analyzed. Patients with BW ≤2,500, 2,500–4,000, and ≥4,000 g were considered as having low BW (LBW), normal BW (NBW), and high BW (HBW), respectively. Testicular volume (TV) was assessed with a Prader orchidometer. Serum hormones were measured in all cases. Semen analyses were categorized based on 2021 World Health Organization reference criteria. Sperm DNA fragmentation (SDF) was tested in every patient and considered pathological for SDF >30%. ART outcomes were available for 282 (26.5%) patients. Descriptive statistics and logistic regression analyses detailed the association between semen parameters and clinical characteristics and the defined BW categories. Results: Of all, LBW, NBW, and HBW categories were found in 79 (7.5%), 807 (76.0%), and 177 (16.5%) men, respectively. LBW men had smaller TV, presented higher follicle-stimulating hormone (FSH) but lower total testosterone levels compared to other groups (all p<0.01). Sperm progressive motility (p=0.01) and normal morphology (p<0.01) were lower and SDF values were higher (all p<0.01) in LBW compared to other groups. ART pregnancy outcomes were lower in LBW compared to both NBW and HBW categories (26.1% vs. 34.5% vs. 34.5%, p=0.01). At multivariable logistic regression analysis, LBW was associated with SDF >30% (odd ratio [OR] 3.7; p<0.001), after accounting for age, Charlson Comorbidity Index (CCI), FSH, and TV. Similarly, LBW (OR 2.2; p<0.001), SDF >30% (OR 2.9; p<0.001) and partner’s age (OR 1.3; p=0.001) were associated with negative ART outcomes, after accounting for the same predictors. Conclusions LBW was associated with impaired clinical and semen characteristics in infertile men compared to both NBW and HBW. SDF and ART outcomes were significantly worse in the LBW group.

Purpose: Augmented adiposity may negatively impact sexual sphere through its metabolic effects and its detrimental impact on reproductive hormones. Moreover, a dysregulated metabolic pathway may promote apoptosis among spermatogenic cells. Based on these premises, a relation between weights loss and ameliorate semen parameters seems beneficial. To investigate if physical activity may affect semen parameters and fertility rate, a systematic literature search on major dataset has been performed. Materials and Methods: The search terms included: “Assisted reproduction therapies,” “fertility,” “semen parameters,” “sperm parameters,” and “physical activity.” This analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines and it was registered on PROSPERO (CRD42023384471). A total of 47 studies have been identified; 1 reference has been eliminated after duplication check. After preliminary screening 32 papers have been excluded. Considering the exclusion criteria, 15 full-text articles were evaluated for eligibility. After a full-text review, six studies published during a span of eight years (2014–2022) have been included in the meta-analysis. Semen parameters, pregnancy and birth rates were investigated. The revised Cochrane risk of bias tool (Rob2) has been used to check the risk of bias. Results: The number of patients enrolled in studies ranges from 17 to 521; in the end, a total of 1,637 patients have been enrolled in the study. Fertility parameters investigated were semen quality parameters and pregnancy rates and live births. A statistically significant relationship between physical exercise and sperm concentration (p=0.02), total sperm motility (p<0.01), total sperm count (p<0.01), normal morphology (p<0.01) has been established. Moreover, the study registered a statistically significant association within physical activity and total pregnancy rate (p<0.01) and live birth rate (p<0.01). Conclusions We demonstrated that physical activity is significantly associated with amelioration of semen parameters and may be crucial in improving or even reverting male infertility.

Purpose: In industrialized countries, air pollutants levels have been monitored closely for environmental and research issues. Using Italian data, we aimed to investigate the association between air pollutants levels and semen parameters in a cohort of non-Finnish white-European men presenting for couple’s infertility. Materials and Methods: Complete demographic and laboratory data from 1,152 infertile men consecutively assessed between January 2015 and January 2018 were analyzed. Semen analyses were based on the 2010 World Health Organization reference criteria. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). We analyzed the annual average level of the three main markers of air pollution (Pm10, Pm2.5, and NO2) between 2014 and 2018. Descriptive statistics, linear and logistic regression analyses tested the association between air pollutants levels and semen parameters. Results: Of 1,152 men, 87 (7.55%) had normal sperm parameters at first semen analysis. Of 1,065 patients with abnormal semen analyses, 237 (22.25%), 324 (30.42%), and 287 (26.95%) patients presented 1, 2 or 3 abnormalities, respectively, and 217 (20.38%) were azoospermic. At linear regression analysis, Pm10, Pm2.5, and NO2 were negatively associated with sperm morphology (Pm10: β=-0.5288 µg/m3, p=0.001; Pm2.5: β=-0.5240 µg/m3, p=0.019; NO2: β=-0.4396 µg/m3, p<0.0001). Furthermore, the adjusted odds of normal sperm morphology <4% were 1.06 (95% confidence interval [CI], 1.03–1.09; p=0.007) for Pm10, 1.07 (95% CI, 1.03–1.11; p=0.007) for Pm 2.5, and 1.03 (95% CI, 1.02–1.05; p=0.001) for NO2, respectively. Conclusions In a large homogenous cohort of infertile men, Pm10, Pm 2.5, and NO2 levels were negatively associated with sperm morphology. Conversely, no clear association was observed with other macroscopic sperm parameters.

Purpose: Overall, male factor infertility (MFI) accounts for up to 50% of etiologies of couple’s infertility, with almost 30% of MFI cases being idiopathic in nature. Idiopathic MFI does not support a tailored treatment work-up in clinical practice. To investigate rates of and characteristics of men presenting for idiopathic versus unexplained primary infertility as compared with same-ethnicity, age-comparable fertile men. Materials and Methods: Demographic, clinical and laboratory data from 3,098 primary infertile men consecutively evaluated were analyzed and compared with those of 103 fertile controls. Idiopathic male infertility (IMI) was defined for abnormality at semen analysis with no previous history of diseases affecting fertility and normal findings on physical examination and genetic and laboratory testing. Unexplained male infertility (UMI) was defined as infertility of unknown origin with completely normal findings at semen analysis. Descriptive statistics and logistic regression models tested the association between clinical variables and idiopathic infertility status. Results: Overall, 570 (18.5%) and 154 (5.0%) patients depicted criteria suggestive for either IMI or UMI, respectively. Groups were similar in terms of age, BMI, CCI, recreational habits, hormonal milieu, and sperm DNA fragmentation indexes. Conversely, testicular volume was lower in IMI (p<0.001). Vitamin D3 levels were lower in IMI vs. UMI vs. fertile controls (p=0.01). At multivariable logistic regression analysis only vitamin D3 deficiency (OR, 9.67; p=0.03) was associated with IMI. Characteristics suggestive for IMI versus UMI were observed in almost 20% and 5% of men, respectively. Overall, clinical differences between groups were slightly significant and certainly not supportive of a tailored management work-up. Conclusions Current findings further support the urgent need of a more detailed and comprehensive assessment of infertile men to better tailoring their management work-up in the everyday clinical setting.

Since the beginning of the coronavirus disease 19 (COVID-19) pandemic, efforts in defining risk factors and associations between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinical, and molecular features have initiated. After three years of pandemic, it became evident that men have higher risk of adverse outcomes. Such evidence provided the impetus for defining the biological fundaments of such a gender disparity. Our objective was to analyze the most recent literature with the aim of defining the relationship between COVID-19 and fertility, in particular, we assessed the interplay between SARSCoV-2 and testosterone in a systematic review of literature from December 2019 (first evidence of a novel coronavirus in the Hubei province) until March 2022. As a fundamental basis for understanding, articles pertaining preclinical aspects explaining the gender disparity (n=9) were included. The main review categories analyzed the risk of being infected with SARS-CoV-2 according to testosterone levels (n=5), the impact of serum testosterone on outcomes of COVID-19 (n=23), and the impact SARSCoV-2 on testosterone levels after infection (n=19). Preclinical studies mainly evaluated the relation between angiotensinconverting enzyme 2 (ACE2) and its androgen-mediated regulation, articles exploring the risk of COVID-19 according to testosterone levels were few. Although most publications evaluating the effect of COVID-19 on fertility found low testosterone levels after the infection, follow-up was short, with some also suggesting no alterations during recovery. More conclusive findings were observed in men with low testosterone levels, that were generally at higher risk of experiencing worse outcomes (i.e., admission to intensive care units, longer hospitalization, and death). Interestingly, an inverse relationship was observed in women, where higher levels of testosterone were associated to worse outcomes. Our finding may provide meaningful insights to better patient counselling and individualization of care pathways in men with testosterone levels suggesting hypogonadism.