Global, regional, and national burden of diseases associated with male reproduction from 1990 to 2021: a systematic analysis with forecasts to 2050

Abstract

Background

Urogenital congenital anomalies (UCA), Klinefelter syndrome (KS), and male infertility are three diseases inextricably related to male reproduction. It is of paramount importance to conduct a comprehensive and precise analysis of the burden of these three diseases and to predict their future trends.

Methods

We extracted data from the Global Burden of Disease (GBD) database for UCA, KS, and male infertility from 1990 to 2021. Disability-adjusted life-years (DALYs) and prevalence were used to analyze the global, regional, and national burden of these three diseases. The Estimated Annual Percentage Change (EAPC) was used to assess the age-standardized prevalence rates (ASPR) and age-standardized disability-adjusted life years rates (ASDR). Finally, the Auto-Regressive Integrated Moving Average (ARIMA) model was applied to predict the future trends of disease burden.

Results

Over the past 32 years, the ASPR and ASDR of KS and male infertility have shown an increasing trend, which is projected to continue through 2050. Meanwhile, the ASPR of UCA has increased, whereas its ASDR has decreased from 1990 to 2021. In 2021, the fastest increase in the ASPR of male infertility was observed in Low-middle Socio-Demographic Index (SDI) regions, with an EAPC of 1.0 (95% CI 0.6, 1.4). For KS, the highest EAPC of ASPR was in High SDI regions, at 0.1 (95% CI 0.1, 0.2). The most rapid rise in the ASPR of UCA was seen in Middle SDI regions, with an EAPC of 0.2 (95% CI 0.1, 0.2).

Conclusions

UCA, KS, and male infertility have imposed a substantial burden on male reproduction. This situation compels the global community to collaborate in a concerted effort to address these challenges through targeted policies, the development of more streamlined and accurate diagnostic methods, and heightened public awareness.

Introduction

Global fertility rates are decreasing and projected to keep declining, with more than half of countries and territories having fertility rates below replacement levels in 2021 [1]. In this context, poor male reproductive health has become a global issue, and there is a plethora of gaps in the understanding of scholars worldwide [2]. To effectively address this problem, a coordinated and multidisciplinary approach is essential for conducting more comprehensive research on male reproductive-related diseases. Urogenital congenital anomalies (UCA), Klinefelter syndrome (KS), and male infertility are three diseases that significantly compromise male reproductive health [3]. Clinical infertility refers to the inability of a couple to conceive after 12 months of regular unprotected intercourse, with male factors contributing to approximately 30–50% of these cases [4, 5]. UCA, including cryptorchidism, hypospadias and abnormalities of the external genitalia, can directly or indirectly lead to male infertility [6,7,8]. KS is defined by the 47, XXY karyotype and is the most common chromosomal condition in males [9]. Individuals with KS typically present with low testosterone levels, azoospermia, and infertility [10].

It is worth noting that currently, most males have a limited understanding of diseases associated with male reproduction and often do not follow basic recommendations for a healthy lifestyle [11]. Meanwhile, previous studies have shown that clinical evaluations of infertile men by healthcare providers are often suboptimal, with approximately 41% of fertility specialists reporting that they obtain only a brief medical history from male partners and 24% reporting that they never conduct a physical examination on the male partner [12]. Therefore, it is of utmost importance to conduct disease burden analyses of diseases associated with male reproduction at the global, regional, and national levels, thereby raising public awareness of these conditions and guiding public health policies.

Previous research reported that the prevalence of male infertility varies significantly worldwide, ranging from 2 to 12%, with the highest rates in Africa and Eastern Europe [13]. Furthermore, a 2019 study showed that the prevalence and disease burden of UCA are on a continuous upward trend globally, while the prevalence of KS is on a downward trend worldwide [14]. However, presently there is a lack of the most up-to-date epidemiological studies on these diseases associated with male reproduction, and no research has been conducted to integrate these diseases.

The Global Burden of Disease (GBD) Study 2021 is a comprehensive effort to quantify health loss across the globe, analyzing the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in 204 countries and territories from 1990 to 2021 [15]. Based on the GBD 2021 data, we conducted a secondary data analysis of KS, UCA, and male infertility based at global, regional, and national levels from 1990 to 2021. Furthermore, we introduced the Auto-Regressive Integrated Moving Average (ARIMA) model to predict the future trends in the age-standardized prevalence rates (ASPR) and age-standardized disability-adjusted life years rates (ASDR) of these diseases up to 2050.

Method

Data resources and definitions

GBD 2021, which served as the primary data source for this research on the burden of KS, UCA, and male infertility, is a comprehensive epidemiological resource that systematically assesses the health impacts of 371 distinct diseases and injuries, along with 88 risk factors, across 204 countries and territories [15].

The GBD database is currently primarily estimated using Disease Modelling Meta-Regression 2.1 and a meta-analysis integrated estimation for disease burden research [16]. Disease Modelling Meta-Regression 2.1 offers internally consistent estimates of prevalence, incidence, and mortality, all stratified by sex, location, year, and age group. Based on GBD 2019, a complex and comprehensive modeling approach was employed, incorporating Bayesian methods, age-pattern models, and chamber models, which ultimately led to the generation of a highly valuable data structure pattern [17]. The GBD study utilized de-identified data, and the University of Washington Institutional Review Board granted approval for a waiver of informed consent. All this data is accessible for free access through the Global Health Data Exchange (https://vizhub.healthdata.org/gbd-results). The GBD database employs the ICD coding system, with ICD-11 codes for male infertility, KS, and UCA being GB04, LD50.0, and LB70.0, respectively.

Calculating uncertainty

Uncertainty was introduced throughout the GBD estimation process. The 95% uncertainty interval (UI) presented in this study is from GBD 2021, and 95% UI for all estimates are determined using 1000 simulated draws, with the lower and upper bounds defined by the 2.5th and 97.5th percentiles of these draws [16]. The UI calculation harmonizes uncertainties from multiple sources, including input data variability, measurement error correction, and nonsampling error estimation [17].

Sociodemographic index

The Socio-Demographic Index (SDI) is a composite measure of a country’s development status, introduced by the Institute for Health Metrics and Evaluation in 2015 [18]. In the GBD 2021 study, SDI is categorized into five levels: low, low-middle, middle, high-middle, and high. Our analysis was conducted across multiple dimensions, encompassing the national, geographic, SDI regional, and global levels.

Data analysis

In this study, we systematically assessed, described, and analyzed the burden of KS, UCA, and male infertility using a set of key indicators, including the number of prevalent cases, ASPR, DALYs, and ASDR. The DALYs is a comprehensive metric that quantifies the total loss of healthy life years due to disease and disability, allowing for comparisons of health burden across different populations and over time [19]. In addition, we used the Estimated Annual Percentage Change (EAPC) to assess the annual rate of change in health indicators of these diseases. The EAPC is calculated using a linear regression model applied to the natural logarithm of age-standardized rates over time. The model can be represented as:

$$\:y=\alpha\:+\beta\:x+e$$

where: y is the natural logarithm of the rate, x is the year, α is the intercept, β is the slope of the regression line, and e is the random error. The EAPC is then calculated using the slope (β) of the regression line:

$$\:EAPC=100\times\:\left(\text{exp}\left(\beta\:\right)-1\right)$$

In the calculation of the EAPC, confidence intervals (CI) are derived from the linear regression model used to estimate the beta coefficient. In this study, we used 95% CI to reflect the statistical reliability of the EAPC estimates. When EAPC and the upper limit of its 95% CI are both negative, it indicates a downward trend in the corresponding rate. On the flip side, if both the EAPC and the lower limit of its 95% CI are positive, this suggests an upward trend in the rate.

The ARIMA model—a widely used statistical approach that combines autoregressive, differencing, and moving average components—was employed to project future trends of UCA, KS, and male infertility, utilizing historical epidemiological data from 1990 to 2021 [20]. Finally, statistical analysis and visual representation were performed using R software (version 4.4.2) in this study.

Result

Male infertility

From 1990 to 2021, global male infertility prevalence and DALYs showed consistent growth, with the EAPC of 0.5 (95% CI 0.3,0.6) and 0.5 (95% CI 0.4,0.6) In 2021, the number of prevalence cases and DALYs for male infertility were 55 million and 318 thousand, respectively. Additionally, Negative correlations emerged between the 1990 baseline rates and their subsequent EAPC trends for both ASPR (r = -0.195) and ASDR (r = -0.158) (Table 1 and S1, Fig. 1).

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Regional analyses revealed Andean Latin America with the most rapid ASPR and ASDR increases, with the EAPC of 2.2 (95% CI 1.8, 2.6) and 2.1 (95% CI 1.8, 2.4), respectively. In contrast, Eastern Sub-Saharan Africa and Oceania experienced the most rapid declines in these metrics over the past three decades (Fig. 2). Meanwhile, all SDI regions except Low SDI exhibited rising ASPR and ASDR trends, though High SDI regions maintained the lowest 2021 ASPR. Overall, the SDI levels exhibited no clear linear correlation with the ASPR and ASDR of male infertility, with the highest values observed in High-middle SDI regions, reaching 760.4 (95% UI 438.0, 1242.6) and 4.3 (95% UI 1.6, 10.7) in 2021 (Table 1 and S1, Fig. 3).

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Among the 204 countries and territories globally, India had the highest number of male infertility prevalence cases, reaching 12.4 million in 2021, while Cameroon and Liberia led in ASPR. Interestingly, from 1990 to 2021, the trends in ASPR and ASDR of male infertility were similar in most countries and territories. Malawi, Pakistan, and Uganda had the most significant declines in ASPR and ASDR globally, while the Philippines had the fastest increases in both ASDR and ASPR. (Table 2 and S2, Fig. 4).

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Klinefelter syndrome

Over the past 32 years, the global prevalence and DALYs rates of KS have exhibited a gradual upward trend. Furthermore, the number of prevalent cases has risen from 0.9 million in 1990 to 1.1 million in 2021. In 2021, South Asia accounted for the highest number of prevalence cases of KS, with approximately 0.3 million cases, which exceeded one-quarter of the global total prevalence cases. Meanwhile, Eastern Europe and Western Europe had the highest ASPR globally, while Western Europe, East Asia, and Central Europe have witnessed the most rapid increases in ASPR over the past 32 years. Coincidentally, these three regions have also experienced the fastest rise in ASDR, suggesting that the disease burden of KS is increasing rapidly in these regions (Table S3 and S4, Fig. 2).

From the perspective of the SDI, although there is currently no significant linear correlation between the prevalence of KS and SDI, the absolute number of prevalence cases and the ASPR of KS in high-SDI regions were the highest among the five SDI quintiles in 2021, with a stable annual increase. In contrast, these indices showed a declining trend in low-SDI regions. Similarly, the ASDR of KS exhibited an upward trend in developed regions, whereas it decreased in developing regions (Table S3 and S4, Fig. 3). At the national level, our analysis showed that from 1990 to 2021, among the 204 countries and territories, the ASDR of KS increased in 123 countries and territories, representing approximately three-fifths of the total. Notably, Spain had the most substantial increases in both ASDR and ASPR, with the EAPCs of 1.4 (95% CI 1.2, 1.6) and 1.4 (95% CI 1.2, 1.6), respectively, both of which were markedly higher than the global average. Meanwhile, in 2021, the Netherlands, Portugal, and Belgium recorded the highest ASPR of KS, with values of 32.9 (95% UI 24.9, 41.9), 32.0 (95% UI 24.3, 41.5), and 31.4 (95% UI 24.4, 40.1) per 100,000 population, respectively (Table S5 and S6, Fig. 4).

Urogenital congenital anomalies

From 1990 to 2021, the global prevalence of UCA rose from 5.2 million cases to 6.3 million cases, during which the ASPR increased gradually with an EAPC of 0.1 (95% CI 0.1, 0.1), while the ASDR declined with an EAPC of -0.5 (95% CI -0.6, -0.4). However, despite the overall downward trend of the global ASDR, Oceania has experienced a rapid increase in ASDR over the past three decades, with an EAPC of 2.3 (95% CI 2.2, 2.4), and notably, Andean Latin America, Oceania, and Southern Latin America have emerged as the three regions with the fastest rising ASPR of UCA in the world. In the SDI regions, the ASPR of UCA exhibited a decreasing trend in both the higher and lower SDI regions, while conversely displaying an increasing trend in the Middle SDI regions. Meanwhile, the ASDR demonstrated a downward trajectory across all five SDI regions, with the most rapid decline observed in the higher SDI region (Table S7 and S8, Fig. 2).

The ASPR of UCA has shown an increase in 143 out of 204 countries and territories worldwide, representing more than two-thirds of the total regions, yet despite the reduction in the prevalence of UCA cases in China from 0.7 million to 0.5 million over the past 32 years, China still retains its position as the country with the largest number of UCA cases globally. Meanwhile, Botswana, South Africa, and Eswatini emerged as the three countries with the highest ASPR in 2021. In contrast to the ASPR, the ASDR of UCA has exhibited a declining trend in most countries and territories, with a specific manifestation that out of the global total, 135 countries and territories have experienced a decrease in their ASDR over the period in question (Table S9 and S10, Fig. 4).

Disease forecasting

Our predictive model estimates that the prevalence of male infertility, KS, and UCA will continue to rise in the coming decades, with the global prevalence of these conditions projected to reach approximately 74.5 million for male infertility, 1.4 million for KS, and 7.4 million for UCA by the year 2050. Concurrently, while the prevalence of these conditions is increasing, the DALYs associated with male infertility and KS are also expected to maintain an upward trajectory, whereas the DALYs for UCA are likely to exhibit fluctuations over time (Table S11-13, Fig. 5).

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Discussion

For over half a century, global family-planning policies have predominantly focused on contraception to avert a cascade of issues that arise from overpopulation, including overcrowding, deteriorating sanitation, rampant disease, and environmental degradation [21]. However, in recent decades, the total fertility rate in most countries around the world has plummeted precipitously [22]. This decline, in turn, precipitates a transformation in population structures and engenders profound economic ramifications [21, 23]. In this context, our research has demonstrated that over the past few decades, the prevalence of UCA, KS, and male infertility, which are three diseases associated with male reproduction, has been rising globally. Moreover, previous studies have indicated that there is a general lack of awareness regarding infertility issues among men [24]. This serves as a salient reminder that we must enhance preventive measures for such conditions and strive to achieve early and accurate diagnoses.

We observed that the ASPR and ASDR of male infertility in 1990 were negatively correlated with their subsequent EAPC, which reflects the significant disparities of the disease among different regions worldwide. The highest burden of male infertility is observed in Eastern Europe, while Andean Latin America has witnessed the most rapid increases in ASPR and ASDR, which underscores the urgent need for targeted interventions in these regions. From the perspective of development levels, High-SDI regions also exhibit the highest disease burden of male infertility. The disparities in male infertility could be linked to environmental exposures, including tobacco smoke, pesticides, electromagnetic fields, and ionizing radiation, all of which adversely affect male fertility [25]. Given geographical and economic differences, countries and regions are affected by these exposures to varying extents. Additionally, genetic abnormalities and distinct lifestyle factors, such as smoking, alcohol consumption, and drug use, can also lead to male infertility and may be responsible for the rising male infertility burden in certain regions [26]. Similarly, we found that the disease burden of KS is heavier in regions with higher levels of development. This may be attributed to the capacity for disease diagnosis, as KS is severely underdiagnosed and rarely detected in the early stages, with the majority of patients remaining undiagnosed in childhood [27,28,29]. Attributable to the advancements in prenatal diagnostic techniques, the global ASDR of UCA has exhibited a declining trend over the past 32 years [30, 31]. However, it is imperative to note that significant disparities still exist among regions and countries. For instance, the disease burden of UCA continues to rise in regions such as Andean Latin America, Oceania, and Southern Latin America.

Our projections regarding the future disease burden of male infertility, KS, and UCA underscore an alarming trajectory. According to our forecasts, the disease burden of male infertility is highly likely to continue rising in the future, which is detrimental to social development. This trend could lead to decreased fertility rates, population aging, labor shortages, and a lack of socioeconomic vitality [32]. Moreover, individuals with male infertility are at a higher risk of developing chronic diseases such as diabetes and ischemic heart disease compared to the general population, thereby further exacerbating the societal burden [33]. While KS has a relatively low prevalence rate, it has shown a stable upward trend in the past, and this trajectory is likely to persist in the future. Moreover, given the low diagnosis rate of KS, with only about 25% of affected individuals receiving a diagnosis, and the difficulty in confirming the condition in its early stages, the actual disease burden of KS may be greater than anticipated [27]. Meanwhile, our forecasting results indicate that while the ASPR of UCA is on the rise, the ASDR exhibits a divergent trend. This discrepancy is inextricably linked to the deepening understanding of risk factors associated with UCA and the enhancement and widespread adoption of prenatal diagnostic techniques, which enable clinicians to identify a greater number of potential UCA cases, thereby increasing the ASPR, while early diagnosis and intervention significantly mitigate the ASDR [34,35,36].

Our analysis of UCA, KS and male infertility reveals a worrying future for male reproduction and an urgent need for changes in healthcare systems. The increasing prevalence of UCA and KS, which can lead to male infertility, reveals the importance for policy makers to pay more attention to congenital diseases. For example, prenatal screening and health education for pregnant women can help reduce the burden of congenital diseases, thereby reducing male infertility due to congenital factors [36]. Male infertility is an important factor affecting male reproductive health, and its increasing disease burden and prevalence should be paid more attention. For policy makers, environmental governance should be promoted as environmental pollutants, such as particulate matter, can adversely affect male fertility [37, 38]. In addition, differences between regions are worth noting. Targeted measures are needed in regions with a higher burden of male infertility, such as Eastern Europe, and in regions where the burden has increased more rapidly over the past few decades, such as Andean Latin America. In the perspective of early prevention, lifestyle changes, including exercise and smoking cessation, can improve sperm parameters and the general health of infertile men and should be strongly recommended [39].

However, this study has certain limitations. Firstly, differences in disease definitions and diagnostic criteria across countries and regions may lead to inconsistencies in data collection and analysis. Additionally, variations in data collection, reporting, and recording practices across different areas can result in inconsistent data quality. Notably, the data sources for the GBD did not cover all populations or regions, meaning the findings provide a general overview rather than a comprehensive representation of the studied regions.

Conclusion

The global burden and projections of UCA, KS, and male infertility underscore significant public health concerns regarding male reproduction. To alleviate these burdens and reverse their projected upward trends at the national level, policymakers must acknowledge the status of the continuously rising number of prevalent cases. Moreover, concerted global efforts are also essential, including improving diagnostic methods, enhancing public awareness of these diseases, and identifying more effective treatments.

Data availability

The datasets generated and/or analyzed during the current study are available in the GBD Data Tool repository (http://ghdx.healthdata.org/gbd-results-tool).

References

GBD 2021 Fertility and Forecasting Collaborators. Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the global burden of disease study 2021. Lancet. 2024;403(10440):2057–99. https://doi.org/10.1016/S0140-6736(24)00550-6.

De Jonge CJ, Barratt CLR, Aitken RJ, et al. Current global status of male reproductive health. Hum Reprod Open. 2024;2024(2):hoae017. https://doi.org/10.1093/hropen/hoae017.

Chen T, Belladelli F, Del Giudice F, Eisenberg ML. Male fertility as a marker for health. Reprod Biomed Online. 2022;44(1):131–44. https://doi.org/10.1016/j.rbmo.2021.09.023.

Minhas S, Bettocchi C, Boeri L, et al. European association of urology guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol. 2021;80(5):603–20. https://doi.org/10.1016/j.eururo.2021.08.014.

Eisenberg ML, Esteves SC, Lamb DJ, et al. Male infertility. Nat Rev Dis Primers. 2023;9(1):49. https://doi.org/10.1038/s41572-023-00459-w.

Punjani N, Lamb DJ. Male infertility and genitourinary birth defects: there is more than Meets the eye. Fertil Steril. 2020;114(2):209–18. https://doi.org/10.1016/j.fertnstert.2020.06.042.

Wang X, Liu Q, Zhuang Z, et al. Decoding the pathogenesis of spermatogenic failure in cryptorchidism through single-cell transcriptomic profiling. Cell Rep Med. 2024;5(9):101709. https://doi.org/10.1016/j.xcrm.2024.101709.

van der Horst HJ, de Wall LL. Hypospadias, all there is to know. Eur J Pediatr. 2017;176(4):435–41. https://doi.org/10.1007/s00431-017-2864-5.

Kanakis GA, Nieschlag E. Klinefelter syndrome: more than hypogonadism. Metabolism. 2018;86:135–44. https://doi.org/10.1016/j.metabol.2017.09.017.

Chen X, Zhang X, Jiang T, Xu W. Klinefelter syndrome: etiology and clinical considerations in male infertility†. Biol Reprod. 2024;111(3):516–28. https://doi.org/10.1093/biolre/ioae076.

Jayasena CN, Sharma A, Abbara A, et al. Burdens and awareness of adverse self-reported lifestyle factors in men with sub-fertility: A cross-sectional study in 1149 men. Clin Endocrinol (Oxf). 2020;93(3):312–21. https://doi.org/10.1111/cen.14213.

Olisa NP, Campo-Engelstein L, Martins da Silva S. Male infertility: what on Earth is going on? Pilot international questionnaire study regarding clinical evaluation and fertility treatment for men. Reprod Fertil. https://doi.org/10.1530/RAF-22-0033

Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the Globe. Reprod Biol Endocrinol. 2015;13:37. https://doi.org/10.1186/s12958-015-0032-1.

Shen L, Li J, Zhang H, Zhao Y. Global, regional and National burdens of reproduction-related congenital birth defects, 1990–2019. Front Public Health. 2024;12:1328282. https://doi.org/10.3389/fpubh.2024.1328282.

GBD 2021 Diseases and Injuries Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet. 2024;403(10440):2133–61. https://doi.org/10.1016/S0140-6736(24)00757-8.

GBD 2021 Causes of Death Collaborators. Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet. 2024;403(10440):2100–32. https://doi.org/10.1016/S0140-6736(24)00367-2.

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and National incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392(10159):1789–858. https://doi.org/10.1016/S0140-6736(18)32279-7.

Li X, Cao X, Guo M, Xie M, Liu X, Trends. BMJ. 2020;368:m234. https://doi.org/10.1136/bmj.m234. and risk factors of mortality and disability adjusted life years for chronic respiratory diseases from 1990 to 2017: systematic analysis for the Global Burden of Disease Study 2017.

Wang F, Ma B, Ma Q, Liu X. Global, regional, and National burden of inguinal, femoral, and abdominal hernias: a systematic analysis of prevalence, incidence, deaths, and dalys with projections to 2030. Int J Surg. 2024;110(4):1951–67. https://doi.org/10.1097/JS9.0000000000001071.

Wafa HA, Marshall I, Wolfe CDA, et al. Burden of intracerebral haemorrhage in europe: forecasting incidence and mortality between 2019 and 2050. Lancet Reg Health Eur. 2024;38:100842. https://doi.org/10.1016/j.lanepe.2024.100842.

Fauser BCJM, Adamson GD, Boivin J, et al. Declining global fertility rates and the implications for family planning and family building: an IFFS consensus document based on a narrative review of the literature. Hum Reprod Update. 2024;30(2):153–73. https://doi.org/10.1093/humupd/dmad028.

Vollset SE, Goren E, Yuan CW, et al. Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the global burden of disease study. Lancet. 2020;396(10258):1285–306. https://doi.org/10.1016/S0140-6736(20)30677-2.

Mburu G, Kamuyango A, Kidula N, et al. Fulfilment of fertility desires for the attainment of global sustainable development goals. BMJ Glob Health. 2023;8(4):e012322. https://doi.org/10.1136/bmjgh-2023-012322.

Pedro J, Brandão T, Schmidt L, Costa ME, Martins MV. What do people know about fertility? A systematic review on fertility awareness and its associated factors. Ups J Med Sci. 2018;123(2):71–81. https://doi.org/10.1080/03009734.2018.1480186.

Wdowiak N, Wójtowicz K, Wdowiak-Filip A, et al. Environmental factors as the main hormonal disruptors of male fertility. J Clin Med. 2024;13(7):1986. https://doi.org/10.3390/jcm13071986.

Agarwal A, Baskaran S, Parekh N, et al. Male infertility. Lancet. 2021;397(10271):319–33. https://doi.org/10.1016/S0140-6736(20)32667-2.

Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A. Clinical review: Klinefelter syndrome–a clinical update. J Clin Endocrinol Metab. 2013;98(1):20–30. https://doi.org/10.1210/jc.2012-2382.

Butler G, Srirangalingam U, Faithfull J, Sangster P, Senniappan S, Mitchell R. Klinefelter syndrome: going beyond the diagnosis. Arch Dis Child. 2023;108(3):166–71. https://doi.org/10.1136/archdischild-2020-320831.

Herlihy AS, Halliday JL, Cock ML, McLachlan RI. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust. 2011;194(1):24–8. https://doi.org/10.5694/j.1326-5377.2011.tb04141.x.

Lei TY, Fu F, Li R, et al. Whole-exome sequencing for prenatal diagnosis of fetuses with congenital anomalies of the kidney and urinary tract. Nephrol Dial Transpl. 2017;32(10):1665–75. https://doi.org/10.1093/ndt/gfx031.

Fuchs F, Borrego P, Amouroux C, et al. Prenatal imaging of genital defects: clinical spectrum and predictive factors for severe forms. BJU Int. 2019;124(5):876–82. https://doi.org/10.1111/bju.14714.

De Jonge C, Barratt CLR. The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap. Andrology. 2019;7(6):762–8. https://doi.org/10.1111/andr.12673.

Eisenberg ML, Li S, Cullen MR, Baker LC. Increased risk of incident chronic medical conditions in infertile men: analysis of united States claims data. Fertil Steril. 2016;105(3):629–36. https://doi.org/10.1016/j.fertnstert.2015.11.011.

Zhang Q, Zhang ZC, He XY, Liu ZM, Wei GH, Liu X. Maternal smoking during pregnancy and the risk of congenital urogenital malformations: A systematic review and meta-analysis. Front Pediatr. 2022;10:973016. https://doi.org/10.3389/fped.2022.973016.

Zhang W, Zhou X, Wang W, Wang L, Zhang C, Wang J. Maternal and fetal risk factors for congenital anomalies of the kidney and urinary tract: a birth cohort study in urban China. J Nephrol. 2024;37(9):2521–30. https://doi.org/10.1007/s40620-024-02066-8.

Walker EYX, Winyard P, Marlais M. Congenital anomalies of the kidney and urinary tract: antenatal diagnosis, management and counselling of families. Pediatr Nephrol. 2024;39(4):1065–75. https://doi.org/10.1007/s00467-023-06137-z.

Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev. 2016;96(1):55–97. https://doi.org/10.1152/physrev.00017.2015.

Zhao Y, Zhu Q, Lin J, Cai J. Association of exposure to particulate matter air pollution with semen quality among men in China. JAMA Netw Open. 2022;5(2):e2148684. https://doi.org/10.1001/jamanetworkopen.2021.48684. Published 2022 Feb 1.

Minhas S, Boeri L, Capogrosso P et al. European association of urology guidelines on male sexual and reproductive health: 2025 update on male infertility. Eur Urol https://doi.org/10.1016/j.eururo.2025.02.026