Global Prevalence of Infertility Attributable to Sex Chromosome Abnormalities: Insights from the Global Burden of Disease Study.

Infertility affects approximately 15–20% of couples worldwide. 1 It is estimated that male factors account for 30% to 50% of infertility cases. 2 In 2021, women with infertility accounted for approximately 66.7% of all global infertility cases. 3 In recent years, the incidence of infertility has been on the rise globally, particularly in industrialized regions. Current etiological research indicates inherited genetic abnormalities as one of causes of infertility, 4 with Klinefelter syndrome (KS,47,XXY) and Turner syndrome (TS,45,X) being critical contributors to gonadal dysgenesis. 5 KS is the most common sex chromosome disorder leading to male infertility, 6 with an incidence of about 1 in 500 to 1000 males. 7 KS is typically caused by the nondisjunction of the X chromosome during meiosis, although the specific molecular mechanisms are not yet fully understood. Recent studies suggest that mutations in the Ubiquitin Specific Protease 26 (USP26) gene may interfere with the XY body (a specialized meiotic chromatin structure), leading to the production of a high proportion of XY aneuploid sperm and, consequently, the development of KS. 8 Typical clinical manifestations include small testes, gynecomastia, hypogonadism, and azoospermia, and other systemic symptoms, including impaired metabolic features (obesity, dyslipidemia, insulin resistance), thrombotic predisposition, osteoporosis, etc. 9 Patients with KS are usually unable to conceive naturally, and about 3% of male infertility cases are related to KS. 6 About 14% of Azoospermia cases are related to KS. 10 However, some patients may still achieve parenthood through assisted reproductive technologies, such as micro-testicular sperm extraction (m-TESE) combined with intracytoplasmic sperm injection (ICSI). 11 , 12 TS is one of the most common causes of hypergonadotropic hypogonadism in females, with an incidence of about 1 in 2000 to 2500 female newborns. 13 Patients with TS typically exhibit gonadal dysgenesis, short stature, premature ovarian failure, and infertility due to the early loss of ovarian function. 14 TS can also lead to increased mortality rates. 15 The molecular mechanism may involve haploinsufficiency of certain genes that normally escape X-chromosome inactivation due to the missing X chromosome. Additionally, the missing X chromosome may cause epigenetic changes in other genes, leading to a wide range of clinical symptoms. 16 There is currently no cure for TS, but hormone replacement therapy can help alleviate symptoms of hypogonadism. 17 Similar to male infertility caused by KS, some patients with TS may also achieve fertility through assisted reproductive technologies. 18 Quantitative fluorescent polymerase chain reaction (QF-PCR) and karyotype analysis are commonly employed screening methods. 19 , 20 Early screening is crucial for the treatment of KS. Current evidence indicates that early detection, appropriate medication, and multidisciplinary care are vital to addressing KS-related problems such as infertility and cancer risks. 21 However, only 10% of KS patients are diagnosed before puberty, highlighting a significant screening gap. 22 Therefore, assessing the global infertility burden attributable to KS and TS is urgently needed to inform evidence-based policy-making. Current research primarily focuses on the prevalence of KS and TS. A Danish study revealed that there are 57 cases of KS per 100,000 newborn males and 59 cases of TS per 100,000 newborn females 23 A UK study of 240,000 women reported a TS prevalence of 88 per 100,000, while a US study of 595,612 males found a KS prevalence of 145 per 100,000. 24 Despite extensive epidemiological investigations into KS and TS, research on the disease burden of infertility caused by these conditions remains notably scarce. As reproductive technologies increasingly enable patients with KS and TS to conceive, therefore, conducting a comprehensive global study on the burden of infertility due to KS and TS is a crucial prerequisite for implementing relevant health policies. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) establishes a comprehensive framework to evaluate the impact of infertility across 204 countries and territories, affording valuable insights into emerging trends. This investigation delves into the global prevalence and years lived with disability (YLDs) lost due to infertility caused by KS in men and TS in women, focusing on the reproductive age group of 15 to 49 years. These data were analyzed by age, Socio-demographic index (SDI), regions, and nations, providing new perspectives and insights for epidemiological research on infertility.

The data source for this study is from GBD 2021. The estimates encompassed in the GBD 2021 span 204 countries and territories, grouped into 21 regions and subsequently consolidated into seven super-regions. Estimates for 371 diseases and injuries during the period from 1990 to 2021, including those for females, males, and both sexes combined, are included in the GBD 2021. 25 Based on health data collected from demographic surveillance, administrative reports, scientific research findings, health surveys, medical records, non-medical registries, and numerous other sources, GBD 2021 have conducted detailed estimates for each epidemiological parameter. 25 Other publications have described the methodology used for GBD 2021. 25 , 26 The SDI serves as a comprehensive indicator, encompassing the social and economic development factors that influence the health outcomes of each nation. On the basis of the SDI scores recorded for each country in 2021, they have been divided into five different quintiles: low, low-medium, medium, high-medium and high. In the SDI, the average years of education for persons over 15 years, the lagged income per capita and the total fertility rate for persons under 25 years were taken into account. Higher SDI values are characterised by regions with more advanced socio-economic and demographic progress. 25 According to the case definition of KS (47, XXY) provided within GBD 2021, this condition may be described as a disorder characterised by a male patient being born with an extra X chromosome in all or some of his cells. It should be noted that the present study incorporates a number of other genotypes that possess additional X chromosomes. Meanwhile, TS, known as 45,XO, involves a partial or complete absence of an X chromosome in females. Notably, a subset of TS patients may not exhibit any symptoms. Additional details can be found in the supplementary materials. 25 In GBD 2021, infertility is defined as the inability to conceive a child and subsequently have a live birth through vaginal intercourse without the use of contraceptives. Based on GBD 2021 cause list, several primary causes of infertility were identified, including congenital TS, KS, urogenital anomalies, endometriosis, polycystic ovary syndrome (PCOS), sexually transmitted infections (STIs) and maternal sepsis. Additional details can be found in the appendix of the referenced material. 25 We extracted final GBD 2021 estimates for “Infertility due to Klinefelter syndrome” and “Infertility due to Turner syndrome” from the online Results Tool ( http://ghdx.healthdata.org/gbd-results-tool ). Metrics downloaded comprised ASPR, YLD and AAPC with their 95% uncertainty intervals for individuals aged 15–49 years (split into seven 5-year age bands), both sexes, across 204 countries, 21 GBD regions and 5 SDI region from 1990 to 2021. No additional exclusions or re-modelling were applied. We employed four distinct DisMod-MR 2.1 models to estimate the prevalence of infertility by gender and cause. In this study, the prevalence and YLDs were sourced from GBD 2021. Given that infertility caused by Turner and KS does not lead to death, DALYs—a comprehensive measure of disease burden that includes both YLDs and YLLs—are equivalent to YLDs only in this context. Furthermore, binary study-level covariates were used to minimise error. All rates are per 100,000 with 95% UIs of 1000 estimates. We followed the GATHER guidelines for cross-sectional studies and did not need ethical approval because the data were publicly available and anonymous. We directly extracted data on prevalence cases, YLDs, and their corresponding rates from GBD 2021. The age-standardized prevalence/YLDs rates were directly standardized using the GBD global age-standardized population as the reference. We employed Joinpoint Regression Analysis to identify significant changes in trends and divided the overall trend into multiple segments. Subsequently, AAPC was calculated as a summary measure reflecting the trend over the interval. In addition, the AAPC and its 95% uncertainty interval (UI) were calculated to evaluate the epidemiological trends within each section. If the AAPC and its 95% UI were above or below zero, respectively, the age-standardized rate (ASR) was considered to show an increasing or decreasing trend over time. Furthermore, this study estimated trends across global age groups and health system groups. Given the variations in the distribution of the SDI across countries between 1990 and 2021, we further calculated the distribution of incidence and YLDs for four health system groups and 27 regions. The relationship between AAPC and ASR with SDI was assessed using Spearman correlation analysis. Additionally, the age-standardized prevalence/YLDs distribution and their respective AAPC were analyzed for 204 countries. This study utilized R software (version 4.0.5). A p-value less than 0.05 was considered statistically significant.

At global level, in 1990, there were 329727 prevalent cases (95% UI: 251479–425778) of Kleinfelter syndrome-induced infertility among reproductive-aged men, with an ASPR of 11/100,000 (95% UI: 9–15). By 2021, this number had increased to 473157 (95% UI: 142991–236,948), accompanied by an ASPR of 12/100,000 (95% UI: 9–15) ( Table 1 ). Moreover, there has been a consistent upward trend in the ASPR for infertility over the past 30 years, with an AAPC of 0.09 (95% CI: 0.04–0.13) ( Table 1 and Figure S1A ), which indicates the prevalence of this infertility condition is slowly increasing globally. Table 1 The Prevalence of Male Infertility Impairment Owing to Klinefelter Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels 1990 2021 1990–2021 Prevalent Cases No. (95% UI) ASPR per 100000 No. (95% UI) Prevalent Cases No. (95% UI) ASPR per 100000 No. (95% UI) AAPC No. (95% CI) P Value Global 329727 (251,479–425,778) 11 (9–15) 473,157 (362,419–610,585) 12 (9–15) 0.09 (0.04–0.13) 0.000083 Socio-demographic index Low SDI 28552 (21,543–37,161) 12 (9–15) 69,167 (52,325–90,364) 12 (9–15) −0.01 (−0.03–0.00) 0.142798 Low-middle SDI 67780 (51,249–88,224) 11 (9–15) 119,402 (91,218–154,706) 11 (9–15) −0.03 (−0.05 - −0.01) 0.001246 Middle SDI 95351 (72,153–123,471) 10 (7–13) 132,400 (101,143–170,804) 11 (8–14) 0.29 (0.25–0.32) 0 High-middle SDI 67699 (51,510–87,294) 11 (9–15) 73,285 (55,701–94,776) 12 (9–15) 0.15 (0.05–0.24) 0.001902 High SDI 70064 (53,949–90,700) 15 (12–19) 78,552 (60,318–102,528) 16 (12–21) 0.16 (−0.29–0.62) 0.482121 Region Andean Latin America 2113 (1585–2767) 11 (8–14) 3719 (2827–4841) 10 (8–14) −0.08 (−0.15 - −0.01) 0.033498 Australasia 1114 (843–1463) 10 (8–13) 1501 (1137–1950) 11 (8–14) 0.12 (0.04–0.19) 0.001865 Caribbean 1673 (1268–2169) 9 (7–11) 2146 (1627–2772) 9 (7–12) 0.06 (0.04–0.08) 0 Central Asia 5169 (3926–6694) 15 (11–19) 7269 (5502–9470) 15 (11–19) 0.07 (0.03–0.11) 0.001493 Central Europe 7076 (5379–9109) 11 (9–15) 6215 (4736–8146) 12 (9–16) 0.23 (0.14–0.31) 0 Central Latin America 7541 (5736–9780) 9 (7–11) 11,480 (8716–14,793) 9 (7–11) 0.01 (−0.01–0.02) 0.26845 Central Sub-Saharan Africa 3271 (2441–4371) 12 (9–16) 8629 (6548–11,161) 12 (9–16) 0.01 (−0.04–0.06) 0.670871 East Asia 62599 (46,954–82,129) 8 (6–11) 65,985 (49,588–86,236) 10 (7–13) 0.44 (0.36–0.52) 0 Eastern Europe 20086 (15,204–25,714) 18 (14–23) 16,880 (12,805–21,630) 19 (14–24) 0.13 (0.12–0.15) 0 Eastern Sub-Saharan Africa 11046 (8375–14,399) 12 (9–16) 27,544 (20,858–35,815) 12 (9–16) −0.02 (−0.03 - −0.00) 0.010129 High-income Asia Pacific 10831 (8408–13,866) 12 (9–15) 9282 (7204–11,982) 12 (9–16) −0.03 (−0.05 - −0.00) 0.024817 High-income North America 23646 (17,340–31,596) 16 (12–21) 26,373 (19,361–35,549) 16 (12–21) 0.09 (0.07–0.10) 0 North Africa and Middle East 21270 (16,088–27,523) 12 (9–16) 42,026 (32,172–53,987) 12 (9–15) −0.01 (−0.03–0.00) 0.147334 Oceania 383 (285–506) 11 (8–14) 818 (608–1077) 11 (8–14) 0.02 (−0.00–0.05) 0.081768 South Asia 68979 (52,453–89,631) 12 (9–15) 122,660 (93,150–158,911) 12 (9–15) −0.06 (−0.09 - −0.03) 0.000048 Southeast Asia 25700 (19,448–33,355) 10 (8–13) 38,601 (29,468–50,144) 10 (8–13) 0.01 (0.01–0.02) 0 Southern Latin America 1397 (1050–1801) 6 (4–7) 1919 (1466–2487) 6 (4–7) 0.11 (−0.39–0.61) 0.663477 Southern Sub-Saharan Africa 3519 (2641–4676) 13 (10–17) 5571 (4178–7325) 13 (10–17) −0.00 (−0.01–0.01) 0.969756 Tropical Latin America 5496 (4001–7308) 7 (5–9) 8320 (6135–10,972) 7 (5–9) 0.22 (0.17–0.27) 0 Western Europe 35954 (28,493–46,155) 18 (15–24) 37,595 (29,479–48,396) 20 (16–26) 0.32 (0.29–0.35) 0 Western Sub-Saharan Africa 10863 (8202–14,098) 12 (9–16) 28,623 (21,856–37,193) 12 (9–15) −0.01 (−0.03–0.01) 0.29726 Abbreviations : ASPR, age-standardized prevalence rate; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. The Prevalence of Male Infertility Impairment Owing to Klinefelter Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels Abbreviations : ASPR, age-standardized prevalence rate; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. In 1990, the global YLDs due to male infertility caused by KS were 2474 (95% UI: 1087–5351), with an age-standardized YLDs rate of 0.09 /100,000 (95% UI: 0.04–0.19). By 2021, the YLDs increased to 3548 (95% UI: 1595–7525), while the age-standardized YLDs rate remained at 0.09/100,000 (95% UI: 0.04–0.19). From 1990 to 2021, the global AAPC in the age-standardized YLDs rate was 0.08 (95% CI: 0.05–0.12) ( Table 2 ). Although the absolute value of YLDs increased, the age-standardized YLDs rate remained relatively stable, indicating that the impact of male infertility caused by KS on population health did not significantly worsen in the context of overall population growth ( Table 2 and Figure S1B ). Table 2 The YLD of Male Infertility Impairment Owing to Klinefelter Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels 1990 2021 1990–2021 YLD No. (95% UI) Age-Standardized YLD Rate per 100000 No. (95% UI) YLD No. (95% UI) Age-Standardized YLD Rate per 100000 No. (95% UI) AAPC No. (95% CI) P Value Global 2474 (1087–5351) 0.09 (0.04–0.19) 3548 (1595–7525) 0.09 (0.04–0.19) 0.08 (0.05–0.12) 0.000022 Socio-demographic index Low SDI 214 (94–446) 0.09 (0.04–0.19) 517 (230–1059) 0.09 (0.04–0.18) −0.01 (−0.04–0.02) 0.488486 Low-middle SDI 508 (224–1123) 0.08 (0.04–0.19) 896 (399–1908) 0.08 (0.04–0.18) −0.06 (−0.06 - −0.05) 0 Middle SDI 715 (312–1553) 0.07 (0.03–0.16) 991 (437–2136) 0.08 (0.03–0.17) 0.28 (0.24–0.32) 0 High-middle SDI 508 (227–1093) 0.09 (0.04–0.19) 550 (245–1188) 0.09 (0.04–0.19) 0.15 (0.06–0.24) 0.000831 High SDI 527 (234–1133) 0.11 (0.05–0.24) 591 (256–1304) 0.12 (0.05–0.26) 0.14 (−0.31–0.60) 0.53218 Region Andean Latin America 16 (7–34) 0.08 (0.04–0.17) 28 (12–57) 0.08 (0.03–0.16) −0.08 (−0.24–0.07) 0.301692 Australasia 8 (3–18) 0.08 (0.03–0.16) 11 (4–24) 0.08 (0.03–0.17) 0.15 (0.02–0.28) 0.02682 Caribbean 12 (5–27) 0.07 (0.03–0.14) 16 (7–35) 0.07 (0.03–0.15) 0.07 (0.02–0.12) 0.003295 Central Asia 39 (17–85) 0.11 (0.05–0.24) 55 (23–114) 0.11 (0.05–0.23) 0.07 (−0.00–0.14) 0.063248 Central Europe 53 (24–117) 0.08 (0.04–0.18) 47 (20–101) 0.09 (0.04–0.2) 0.22 (0.12–0.32) 0.000029 Central Latin America 57 (24–125) 0.07 (0.03–0.14) 86 (36–190) 0.07 (0.03–0.14) 0.02 (−0.02–0.05) 0.375522 Central Sub-Saharan Africa 25 (10–53) 0.09 (0.04–0.19) 64 (27–131) 0.09 (0.04–0.18) −0.02 (−0.05–0.01) 0.275019 East Asia 470 (202–1024) 0.06 (0.03–0.14) 494 (212–1061) 0.07 (0.03–0.16) 0.43 (0.33–0.53) 0 Eastern Europe 151 (67–318) 0.14 (0.06–0.29) 127 (57–282) 0.14 (0.06–0.31) 0.13 (0.09–0.17) 0 Eastern Sub-Saharan Africa 83 (36–180) 0.09 (0.04–0.2) 205 (91–420) 0.09 (0.04–0.19) −0.03 (−0.09–0.02) 0.241571 High-income Asia Pacific 82 (33–170) 0.09 (0.04–0.18) 69 (29–149) 0.09 (0.04–0.19) −0.03 (−0.08–0.02) 0.202932 High-income North America 178 (76–389) 0.12 (0.05–0.26) 199 (86–452) 0.12 (0.05–0.27) 0.09 (0.05–0.12) 0.000004 North Africa and Middle East 160 (70–351) 0.09 (0.04–0.2) 316 (143–646) 0.09 (0.04–0.18) −0.01 (−0.04–0.02) 0.563786 Oceania 3 (1–6) 0.08 (0.03–0.18) 6 (2–14) 0.08 (0.03–0.18) 0.04 (−0.06–0.15) 0.410525 South Asia 517 (225–1144) 0.09 (0.04–0.2) 919 (406–1926) 0.09 (0.04–0.18) −0.06 (−0.08 - −0.05) 0 Southeast Asia 192 (82–420) 0.08 (0.03–0.17) 289 (125–627) 0.08 (0.03–0.17) 0.02 (−0.03–0.07) 0.462038 Southern Latin America 11 (4–22) 0.04 (0.02–0.09) 14 (6–32) 0.04 (0.02–0.09) 0.12 (−0.13–0.38) 0.330388 Southern Sub-Saharan Africa 26 (11–57) 0.1 (0.04–0.21) 42 (18–87) 0.1 (0.04–0.2) −0.01 (−0.02 - −0.00) 0.029048 Tropical Latin America 41 (17–88) 0.05 (0.02–0.11) 63 (27–137) 0.05 (0.02–0.12) 0.22 (0.13–0.31) 0.000001 Western Europe 270 (120–571) 0.14 (0.06–0.29) 283 (124–617) 0.15 (0.07–0.33) 0.34 (0.28–0.41) 0 Western Sub-Saharan Africa 81 (35–172) 0.09 (0.04–0.19) 215 (96–451) 0.09 (0.04–0.19) −0.02 (−0.07–0.04) 0.526833 Abbreviations : YLD, years lived with disability; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. The YLD of Male Infertility Impairment Owing to Klinefelter Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels Abbreviations : YLD, years lived with disability; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. Meanwhile, female infertility associated with TS shows an opposite trend. In 1990, there were 181173 prevalent cases of TS-induced female infertility among reproductive-aged women, with an ASPR of 6.55/100,000 persons (95% UI: 5.16–8.55). By 2021, this number had significantly increased to 245550 cases, accompanied by an ASPR of 6.3/100,000 (95% UI: 4.93–8.24) ( Table 3 ). There has been a continuous downward trend in the ASPRs for infertility, with an AAPC of −0.012 (95% CI: −0.13 - −0.11) ( Table 3 ). Although the number of prevalent cases has increased, the decline in ASPR indicates that the age-standardized prevalence rate of female infertility is slowly decreasing on a global scale ( Table 3 and Figure S1C ). Table 3 The Prevalence of Female Infertility Impairment Owing to Turner Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels 1990 2021 1990–2021 Prevalent Cases No. (95% UI) ASPR per 100000 No. (95% UI) Prevalent Cases No. (95% UI) ASPR per 100000 No. (95% UI) AAPC No. (95% CI) P Value Global 181173 (142,991–236,948) 6.55 (5.16–8.55) 245,550 (192,054–321,103) 6.3 (4.93–8.24) −0.12 (−0.13 - −0.11) 0 Socio-demographic index Low SDI 13692 (10,516–17,954) 5.6 (4.27–7.33) 33,236 (25,350–43,782) 5.58 (4.25–7.32) −0.00 (−0.01–0.01) 0.939598 Low-middle SDI 32257 (24,999–42,442) 5.5 (4.27–7.24) 57,326 (44,025–75,632) 5.49 (4.22–7.23) −0.01 (−0.02 - −0.01) 0 Middle SDI 46754 (35,824–62,098) 4.94 (3.78–6.56) 63,473 (49,139–83,555) 5.21 (4.03–6.86) 0.17 (0.16–0.18) 0 High-middle SDI 36835 (28,921–48,395) 6.48 (5.09–8.53) 37,636 (29,569–49,215) 6.39 (5.03–8.36) −0.00 (−0.01–0.00) 0.21818 High SDI 51470 (40,910–65,794) 11.34 (9.01–14.49) 53,694 (42,684–69,097) 11.32 (9.01–14.55) −0.06 (−0.08 - −0.04) 0 Region Andean Latin America 999 (773–1295) 4.95 (3.83–6.43) 1688 (1296–2164) 4.79 (3.68–6.15) −0.11 (−0.11 - −0.10) 0 Australasia 826 (650–1080) 7.66 (6.02–10.01) 1102 (864–1436) 7.76 (6.09–10.1) 0.05 (0.03–0.06) 0 Caribbean 1019 (801–1341) 5.21 (4.09–6.87) 1234 (963–1634) 5.12 (4–6.78) −0.06 (−0.07 - −0.04) 0 Central Asia 2753 (2161–3586) 7.77 (6.1–10.13) 3919 (3005–5135) 8.11 (6.22–10.66) 0.14 (0.13–0.15) 0 Central Europe 4374 (3449–5713) 7.12 (5.62–9.3) 3700 (2903–4820) 7.44 (5.88–9.69) 0.14 (0.11–0.17) 0 Central Latin America 4558 (3542–5970) 5.11 (3.97–6.7) 6821 (5323–8909) 4.98 (3.89–6.5) −0.08 (−0.12 - −0.03) 0.000665 Central Sub-Saharan Africa 1571 (1182–2069) 5.76 (4.33–7.6) 4048 (3046–5361) 5.7 (4.26–7.53) −0.02 (−0.04–0.01) 0.254381 East Asia 30388 (23,384–40,526) 4.37 (3.36–5.83) 30,546 (23,820–40,392) 4.79 (3.74–6.31) 0.29 (0.27–0.31) 0 Eastern Europe 10490 (8164–13,726) 9.52 (7.4–12.48) 8708 (6850–11,443) 9.56 (7.5–12.58) 0.01 (−0.00–0.03) 0.075171 Eastern Sub-Saharan Africa 5621 (4264–7406) 5.79 (4.4–7.63) 13,731 (10,407–18,074) 5.81 (4.44–7.62) 0.01 (0.00–0.02) 0.018938 High-income Asia Pacific 8722 (6997–11,196) 9.55 (7.65–12.26) 6881 (5520–8803) 9.36 (7.5–11.99) 0.02 (0.02–0.03) 0 High-income North America 21801 (17,134–28,253) 14.7 (11.56–19.03) 24,608 (19,372–31,959) 14.8 (11.64–19.24) −0.05 (−0.06 - −0.04) 0 North Africa and Middle East 5985 (4617–7921) 3.6 (2.78–4.77) 11,383 (8807–15,006) 3.55 (2.75–4.68) −0.04 (−0.06 - −0.03) 0 Oceania 181 (138–240) 5.42 (4.12–7.17) 390 (295–514) 5.42 (4.11–7.15) −0.01 (−0.03–0.02) 0.546957 South Asia 30186 (23,333–39,675) 5.55 (4.3–7.28) 56,168 (43,127–73,815) 5.54 (4.26–7.29) 0.00 (−0.02–0.03) 0.654162 Southeast Asia 15438 (12,091–20,353) 6.05 (4.73–8) 21,119 (16,385–27,712) 5.79 (4.49–7.59) −0.14 (−0.18 - −0.10) 0 Southern Latin America 2525 (1952–3330) 9.99 (7.72–13.17) 3550 (2771–4650) 10.23 (7.98–13.39) 0.07 (0.04–0.10) 0.000004 Southern Sub-Saharan Africa 1771 (1357–2315) 5.99 (4.6–7.81) 2661 (2053–3514) 6.02 (4.65–7.96) 0.02 (0.02–0.03) 0 Tropical Latin America 5360 (4098–7090) 6.41 (4.92–8.46) 8031 (6242–10,644) 6.72 (5.23–8.93) 0.15 (0.13–0.17) 0 Western Europe 21073 (16,939–26,326) 11 (8.84–13.74) 20,361 (16,081–26,248) 11.16 (8.83–14.41) 0.05 (0.03–0.06) 0 Western Sub-Saharan Africa 5532 (4276–7290) 5.73 (4.41–7.55) 14,902 (11,405–19,588) 5.7 (4.37–7.5) −0.02 (−0.05–0.00) 0.079283 Abbreviations : ASPR, age-standardized prevalence rate; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. The Prevalence of Female Infertility Impairment Owing to Turner Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels Abbreviations : ASPR, age-standardized prevalence rate; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. In 1990, the global YLDs due to female infertility caused by TS were 1358 years (95%UI: 557–2750), with an age-standardized YLDs rate of 0.05/100,000 (95% UI: 0.02–0.1). By 2021, the YLDs increased to 1840 years (95% UI:769–3736), while the age-standardized YLDs rate remained at 0.05/100,000 (95% UI:0.02–0.1). From 1990 to 2021, the global AAPC in the age-standardized YLDs rate was −0.12 (95% UI: −0.13 - −0.11) ( Table 4 ). Despite the increase in the absolute number of YLDs, the significant decline in the age-standardized YLDs rate indicates that the impact of female infertility caused by TS on population health has improved in the context of overall population growth ( Table 4 and Figure S1D ). Table 4 The YLD of Female Infertility Impairment Owing to Turner Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels 1990 2021 1990–2021 YLD No. (95% UI) Age-Standardized YLD Rate per 100000 No. (95% UI) YLD No. (95% UI) Age-Standardized YLD Rate per 100000 No. (95% UI) AAPC No. (95% CI) P Value Global 1358 (557–2750) 0.05 (0.02–0.1) 1840 (769–3736) 0.05 (0.02–0.1) −0.12 (−0.13 - −0.11) 0 Socio-demographic index Low SDI 103 (42–211) 0.04 (0.02–0.09) 249 (105–515) 0.04 (0.02–0.09) 0.00 (−0.02–0.02) 0.996903 Low-middle SDI 242 (97–505) 0.04 (0.02–0.09) 430 (185–884) 0.04 (0.02–0.08) −0.02 (−0.06–0.02) 0.379058 Middle SDI 351 (144–697) 0.04 (0.02–0.07) 476 (201–957) 0.04 (0.02–0.08) 0.16 (0.15–0.18) 0 High-middle SDI 276 (114–560) 0.05 (0.02–0.1) 282 (116–564) 0.05 (0.02–0.1) −0.01 (−0.04–0.02) 0.573862 High SDI 385 (160–780) 0.08 (0.04–0.17) 402 (170–808) 0.08 (0.04–0.17) −0.08 (−0.16 - −0.00) 0.043046 Region Andean Latin America 7 (3–15) 0.04 (0.02–0.07) 13 (5–26) 0.04 (0.01–0.07) −0.11 (−0.15 - −0.06) 0.000002 Australasia 6 (3–13) 0.06 (0.02–0.12) 8 (3–17) 0.06 (0.02–0.12) 0.01 (−0.08–0.10) 0.89337 Caribbean 8 (3–15) 0.04 (0.02–0.08) 9 (4–19) 0.04 (0.02–0.08) −0.06 (−0.08 - −0.05) 0 Central Asia 21 (8–42) 0.06 (0.02–0.12) 29 (12–59) 0.06 (0.02–0.12) 0.12 (0.05–0.19) 0.000421 Central Europe 33 (13–65) 0.05 (0.02–0.11) 28 (11–56) 0.06 (0.02–0.11) 0.14 (0.09–0.19) 0 Central Latin America 34 (14–70) 0.04 (0.02–0.08) 51 (21–103) 0.04 (0.02–0.08) −0.07 (−0.12 - −0.03) 0.000596 Central Sub-Saharan Africa 12 (5–26) 0.04 (0.02–0.09) 30 (12–67) 0.04 (0.02–0.09) −0.02 (−0.03 - −0.00) 0.010452 East Asia 229 (94–457) 0.03 (0.01–0.07) 230 (96–463) 0.04 (0.02–0.07) 0.29 (0.27–0.32) 0 Eastern Europe 78 (33–162) 0.07 (0.03–0.15) 65 (27–131) 0.07 (0.03–0.14) 0.02 (−0.03–0.07) 0.500545 Eastern Sub-Saharan Africa 42 (17–84) 0.04 (0.02–0.09) 103 (44–214) 0.04 (0.02–0.09) 0.02 (−0.02–0.05) 0.335575 High-income Asia Pacific 65 (27–134) 0.07 (0.03–0.15) 51 (22–105) 0.07 (0.03–0.14) 0.02 (−0.01–0.06) 0.198772 High-income North America 163 (67–330) 0.11 (0.05–0.22) 184 (75–369) 0.11 (0.04–0.22) −0.05 (−0.08 - −0.02) 0.002405 North Africa and Middle East 45 (19–91) 0.03 (0.01–0.06) 86 (36–172) 0.03 (0.01–0.05) −0.05 (−0.06 - −0.03) 0 Oceania 1 (1–3) 0.04 (0.02–0.08) 3 (1–6) 0.04 (0.02–0.09) −0.02 (−0.11–0.07) 0.67193 South Asia 226 (92–472) 0.04 (0.02–0.09) 421 (179–869) 0.04 (0.02–0.09) −0.00 (−0.03–0.03) 0.963456 Southeast Asia 116 (48–232) 0.05 (0.02–0.09) 158 (66–320) 0.04 (0.02–0.09) −0.15 (−0.21 - −0.10) 0 Southern Latin America 19 (8–39) 0.08 (0.03–0.16) 27 (10–53) 0.08 (0.03–0.15) 0.04 (−0.08–0.17) 0.491612 Southern Sub-Saharan Africa 13 (5–27) 0.04 (0.02–0.09) 20 (9–41) 0.05 (0.02–0.09) 0.03 (−0.01–0.07) 0.167013 Tropical Latin America 40 (16–82) 0.05 (0.02–0.1) 60 (25–121) 0.05 (0.02–0.1) 0.15 (0.11–0.20) 0 Western Europe 158 (68–327) 0.08 (0.04–0.17) 152 (65–312) 0.08 (0.04–0.17) 0.04 (−0.04–0.11) 0.306093 Western Sub-Saharan Africa 41 (17–86) 0.04 (0.02–0.09) 112 (48–224) 0.04 (0.02–0.09) −0.02 (−0.05–0.00) 0.059054 Abbreviations : YLD, years lived with disability; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. The YLD of Female Infertility Impairment Owing to Turner Syndrome and Their AAPCs from 1990 to 2021 at the Global and Regional Levels Abbreviations : YLD, years lived with disability; AAPC, average annual percentage change; UI, uncertainty interval; SDI, Socio-demographic index. Overall, the prevalence of male infertility induced by KS gradually decreases with increasing age, and there is a slight increase in prevalence when comparing the rates from 2021 to 1990. In terms of age structure, high-middle SDI regions show a trend of reduced proportion among young people (aged 15–29). There are no significant changes in the age structure of prevalence in other SDI regions. In contrast, there was a noticeable increase in the proportion of younger patients (15–29 years) in the region with low SDI ( Figure 1A ). However, the YLDs within the same SDI region showed no significant change between 1990 and 2021 ( Figure S2A ). Figure 1 The changes in the prevalence rates of male infertility globally and across different levels of the SDI from 1990 to 2021. ( A ) Prevalence rates of male infertility. ( B ) Prevalence rates of female infertility. Abbreviations : ASPR, age-standardized prevalence rate; SDI, Socio-demographic index. The changes in the prevalence rates of male infertility globally and across different levels of the SDI from 1990 to 2021. ( A ) Prevalence rates of male infertility. ( B ) Prevalence rates of female infertility. For women infertility attributed to TS, The prevalence gradually decreases with increasing age. Overall, there has been a slight increase in the global prevalence rates between 1990 and 2021 ( Figure 1B ). Similar to male infertility induced by KS, the high-middle SDI regions also show a trend of decreasing proportion of prevalence among younger patients (aged 15–29), while there are no significant changes in the age distribution of prevalence in the remaining SDI regions, and when comparing the YLDs across all age groups in 2021 to those in 1990, there are no significant changes ( Figure S2A ). For KS-induced male infertility, we found there is a clear positive correlation between SDI and both incidence rates and YLDs when SDI is between 0.6 and 0.8. But this correlation becomes negative when SDI exceeds 0.8 ( Figures 2A and S3A ). High SDI areas typically have a higher number of prevalent cases and ASPR, but the rate of increase is slower. In 2021, the ASPR in high SDI areas was 16/100,000. Compared to the data from 1990, the low-middle SDI region demonstrated a slight decline in the ASPR, with an AAPC of −0.03 (95% CI: −0.05 - −0.01). In the meanwhile, the middle and the middle-high SDI region demonstrated a significant increase in the ASPR, with an AAPC of 0.29 (95% CI: 0.25–0.32) and 0.15 (95% Cl: 0.05–0.24) respectively during the same period ( Table 1 ). Similar, the YLDs in various regions exhibited comparable trends. There was a slight decrease in YLDs in low-middle SDI regions, with an AAPC of −0.06 (95% CI: −0.06 - −0.05). In contrast, YLDs in middle SDI and middle-high SDI regions showed a more pronounced increase, with AAPCs of 0.28 (95% CI: 0.24–0.32) and 0.15 (95% CI: 0.06–0.24), respectively ( Table 2 ). By analyzing the annual prevalence and YLDs of male infertility caused by KS from 1990 to 2021, we found that between 2000 and 2010, there was a peak in the prevalence and YLDs of male infertility in high SDI regions. After falling back to previous levels in 2010, the figures began to rise gradually again ( Figure S1A ). Figure 2 Global and Regional Relationships between SDI and YLDs of Infertility. ( A ) Relationship between male infertility prevalence and SDI. ( B ) Relationship between female infertility prevalence and SDI. Abbreviations : ASPR, age-standardized prevalence rate; SDI, Socio-demographic index. Global and Regional Relationships between SDI and YLDs of Infertility. ( A ) Relationship between male infertility prevalence and SDI. ( B ) Relationship between female infertility prevalence and SDI. For TS-induced female infertility, Similar to male infertility, there is a clear positive correlation between SDI and both incidence rates and YLDs when SDI is bigger than 0.5 ( Figures 2B and S3B ), High SDI regions had a higher ASPR (11.32/100,000, 95% UI:9.01–14.55) than the other SDI regions. Compared to the data from 1990, the low-middle SDI regions demonstrated a slight decline in the ASPR, with an AAPC of −0.12 (95% CI: −0.13 - −0.11). In the meanwhile, the middle SDI region demonstrated a significant increase in the ASPR, with an AAPC of 0.17 (95% Cl: 0.16–0.18) during the same period ( Table 3 ). In regions with high SDI and high-middle SDI levels, the proportion of younger patients has significantly decreased, and the peak prevalence age group tends to shift towards middle-aged populations ( Figure 1B ). Similar, the YLDs in various regions exhibited comparable trends. There was a slight decrease in YLDs in high SDI regions, with an AAPC of −0.08 (95% CI: −0.16 - −0.00). In contrast, YLDs in middle SDI regions showed a notable increase, with AAPC of 0.16 (95% CI:0.15–0.18) ( Table 4 ). Similar to men infertility induced by KS, we noticed a significant decrease in the proportion of younger patients (15–29 years) suffered women infertility induced by TS in the region with middle to high SDI, and there was also a noticeable increase in the proportion of younger patients (15–29 years) in the region with low SDI. The peak prevalence age group tends to shift towards the middle-aged population. The YLDs within the same SDI region showed no significant change between 1990 and 2021 ( Figure S2B ). Epidemiological analysis of GBD 2021 data revealed distinct SDI-related stratification in sex chromosome disorder-associated infertility. In 2021, for KS-related male infertility burden, middle SDI regions exhibited the highest prevalence concentration, with Western Europe (37,595 cases; 95% UI: 29,479–48,396), Eastern Europe (16,880; 95% UI:12,805–21,630), and High-income North America (26,373; 95% UI:19,361–35,549) representing the most affected areas ( Table 1 and Figure S4A ). Conversely, TS-mediated female infertility displayed parallel geographic disparities, though with differential regional gradients. Despite similar SDI stratification patterns, the predominant burden localized to High-income North America (24,608; 95% UI:19,372–31,959), Western Europe (20,361; 95% UI:6081–26,248), and Southern Latin America (3550; 95% UI:2771–4650), collectively accounting for 61.3% of global female cases ( Table 3 and Figure S4A ). Based on the data from 2021, the regions with the highest prevalence of male infertility induced by KS are Western Europe (20/100,000,95% UI:16–26), Eastern Europe (19/100,000,95% UI:14–24) and High-income North America (16/100,000,95% UI:12–21), while the lowest prevalence is in Southern Latin America (6/100,000, 95% UI:4–7), Tropical Latin America (7/100,000, 95% UI:5–9) and the Caribbean (9/100,000, 95% UI:7–12). The regions with the fastest increase in prevalence are East Asia (0.44, 95% UI:0.36–0.52), Western Europe (0.32, 95% UI:0.29–0.35) and Central Europe (0.23, 95% UI:0.14–0.31), whereas the region with the fastest decrease is Andean Latin America (−0.08, 95% UI:-0.15 - −0.01) ( Table 1 ). The highest YLDs are Western Europe (0.15, 95% UI: 0.07–0.33) and Eastern Europe (0.14,95% UI: 0.06–0.31), while the lowest YLDs are in Tropical Latin America (0.05,95%UI:0.02–0.12), the Caribbean (0.07, 95% UI: 0.03–0.15), and East Asia (0.07, 95%UI: 0.03–0.16) ( Table 2 and Figure S4B ). For female infertility induced by TS, the regions with the highest prevalence are High-income North America (14.8, 95% UI: 11.64–19.24) and Western Europe (11.16, 95% UI: 8.83–14.41), while the lowest prevalence is in North Africa and the Middle East (3.55, 95% UI: 2.75–4.68), East Asia (4.79, 95% UI: 3.74–6.31), and Andean Latin America (4.79, 95% UI: 3.68–6.15). The region with the fastest increase in prevalence is East Asia (0.29, 95% CI: 0.27–0.31), whereas the region with the fastest decrease is Southeast Asia (−0.14, 95% CI: −0.18 - −0.10) ( Table 3 ). The highest YLDs are in High-income North America (0.11; 95% UI: 0.04–0.22), while the lowest YLDs are in North Africa and the Middle East (0.03, 95% UI: 0.01–0.05), and East Asia (0.04, 95% UI: 0.02–0.07). The fastest increase in YLDs is in East Asia (0.29, 95% CI:0.27–0.32), and the fastest decrease is in Andean Latin America (−0.11, 95% CI:-0.15 - −0.06) ( Table 4 and Figure S4B ). According to 2021 data, countries with the highest prevalence of male infertility caused by KS are primarily located in Netherlands (31.47), Portugal (29.53), Belgium (29.44). Countries with the lowest prevalence include Argentina (4.25), Uruguay (6.08) and Paraguay (7.1) ( Table S1 and Figure 3A ). The fastest-growing prevalence rates are observed in France (0.79), Spain (0.65), China (0.46). While, the lowest-growing prevalence rates are observed in Taiwan (Province of China) (−0.22), Nepal (−0.15), Ecuador (−0.13) ( Table S2 and Figure 3B ). The highest YLDs due to male infertility are concentrated in Netherlands (0.24), Belgium (0.22) and Ireland (0.22). The lowest YLDs due to male infertility are concentrated in Argentina (0.03), Paraguay (0.05) and Brazil (0.05) ( Table S3 and Figure S5A ). The fastest increases in YLDs are seen in France (0.77), Spain (0.65) and China (0.45), while the most significant declines occur in the Nepal (−0.22), Taiwan (Province of China)(−0.21) and Palestine (−0.15) ( Table S4 and Figure S5B ). Figure 3 Global map of 2021 age-standardized rates and corresponding average annual percentage changes from 1990 to 2021 for male infertility attributable to Klinefelter syndrome. ( A ) The ASPR of male infertility attributable to Klinefelter syndrome in 2021. ( B ) The AAPC of ASPR from 1990 to 2021. ( C ) The ASPR of female infertility attributable to Turner syndrome in 2021. ( D ) The AAPC of ASPR from 1990 to 2021. Abbreviations : ASPR, age-standardized prevalence rate; AAPC, average annual percentage change. Global map of 2021 age-standardized rates and corresponding average annual percentage changes from 1990 to 2021 for male infertility attributable to Klinefelter syndrome. ( A ) The ASPR of male infertility attributable to Klinefelter syndrome in 2021. ( B ) The AAPC of ASPR from 1990 to 2021. ( C ) The ASPR of female infertility attributable to Turner syndrome in 2021. ( D ) The AAPC of ASPR from 1990 to 2021. Regarding female infertility caused by TS, highest-prevalence areas are concentrated in New Zealand (15.55), United States of America (15.15), and Belgium (14.81). Moreover, lowest-prevalence areas are concentrated in Iran (Islamic Republic of)(3.39), Tunisia (3.42) and Kuwait (3.42) ( Table S5 and Figure 3C . The prevalence rates are increasing most rapidly in China (0.3), followed by France (0.22) and Montenegro (0.2). The prevalence rates are decreasing most rapidly in Taiwan (Province of China)(−0.27), Bermuda (−0.26) and Maldives (−0.25) ( Table S6 and Figure 3D ). The highest YLDs linked to female infertility are found in New Zealand (0.12), Belgium (0.11), United States of America (0.11). The lowest YLDs linked to female infertility are found in Sudan (0.03), Yemen (0.03) and Afghanistan (0.03) ( Table S7 and Figure S5C ). The most rapid increases in YLDs occur in China (0.3), Montenegro (0.22) and France (0.21). The most rapid declines in YLDs occur in Taiwan (Province of China)(−0.27), Viet Nam (−0.26), and Bermuda (−0.26) ( Table S8 and Figure S5D ).

To investigate the global prevalence of infertility linked to KS and TS, our study was conducted at global, regional, and national levels, with stratification by age and the SDI. Our findings indicated a modest rise in the global burden of infertility due to KS, whereas the burden of infertility due to TS exhibited a decline during the period from 1990 to 2021. Additionally, both KS and TS exhibited a consistent pattern of decreasing incidence as age increased. It is worth mentioning that the burden of infertility due to both KS and TS increased in regions with middle to high SDI, with particularly higher incidence rates observed in Europe and the United States. The global number of KS cases slightly increased from 1990 to 2021. Prior epidemiological investigations have reported comparable patterns in the worldwide distribution of KS, aligning with our findings. 27 However, in the context of female infertility, a contrary phenomenon can be observed. The global number of TS cases slightly decreased from 1990 to 2021. Previous study observed a similar trend in the global trend of TS. 28 The prevalence of KS is increasing every year due to advances in technology. It has been suggested that a possible explanation for the increased prevalence of KS is the increased frequency of paternal sex chromosome nondisjunction in the MI compartment of spermatogenesis. 27 Given the correlation between GBD data and diagnoses of KS and TS, this rising trend may be attributed to improved screening protocols and rapid expansion of assisted reproductive technology (ART). This pattern aligns with our finding of high KS/TS prevalence in Europe and the United States, while in underdeveloped countries, comparable patient proportions likely remain underdiagnosed due to lack of treatment, resulting in data gaps rather than truly low incidence. Moreover, the majority of TS embryos or fetuses are spontaneously aborted in early and mid-pregnancy 29 , 30 and there is a decreasing trend in the prevalence of TS due to an increase in the rate of induced abortions. 23 Additionally, The differing incidence rates between KS and TS may also correlate with their distinct phenotypic presentations. KS often remains clinically asymptomatic until adulthood, while typical features of TS are typically identified in childhood or even prenatally. 31 This phenotypic asymmetry further widens the observed prevalence gap between the two syndromes. In our study, patients with infertility caused by TS and KS tended to be younger. This is consistent with the fact that the average age at TS diagnosis is around 15 years. 16 One explanation for the trend towards younger age at onset of prevalence is that while the majority of patients with KS and TS are diagnosed during adulthood, symptoms can actually manifest during infancy, childhood, or adolescence. 32 Furthermore, studies have indicated that age has emerged as a potential predictor for successful sperm extraction, with higher retrieval rates observed in patients undergoing m-TESE before the age of 35. This enhances the possibility of treating infertility in patients with KS. 33 Considering the median age of diagnosis for KS is 27, 14 this also offers an explanation for the comparatively rare occurrence of infertility in elderly patients with the condition. At the social level, the relationship between delayed childbearing and infertility merits attention. 34 Particularly for patients with KS, diagnosis often only occurs when they are preparing for pregnancy. The current trend of delayed childbearing may further push back the diagnosis age of KS patients, causing them to miss the optimal window for fertility preservation. A positive relationship between SDI and ASPR was observed in this study, aligning with previous research findings. 28 In countries with higher levels of socioeconomic development, there is an enhanced capacity to identify previously undetected cases of KS within the population. 28 Even in developed regions, assisted reproductive technology (ART) treatments for infertility, like in vitro fertilization (IVF), are still underfunded and hard to access due to high costs, social stigma, and limited availability. For fertility preservation in patients with KS, timely screening and diagnosis are crucial. Although technologies for addressing KS-related infertility are advancing, screening for KS remains inadequate, with the average diagnosis age at 27. 14 This often means many KS patients miss the optimal treatment window, further highlighting the importance of early screening for preserving their fertility. Additionally, TS is frequently associated with impairments in social-cognitive processing and executive function. These cognitive abnormalities, coupled with various physical differences, can adversely impact social communication skills, typically leading to a decline in quality of life during early adolescence. 35 Research has shown that individuals diagnosed with TS exhibit a higher incidence and more severe depressive symptoms compared to those without a TS diagnosis. 36 Furthermore, for individuals with TS, notable physical differences such as short stature, shield-like chest, webbed neck, and edema can pose risks stemming from self-perception and fear of others’ reactions. These factors collectively heighten their sense of social shame and hinder their likelihood of seeking medical help. 36 In addition, individuals diagnosed with TS frequently encounter infertility as a prevalent issue. Therapeutic interventions utilising ART are, however, significantly constrained. A matter of significant concern involves the reported potential elevation in mortality rates stemming from aortic dissection or rupture in women with TS who successfully conceive through oocyte donation-facilitated IVF. 37 Notably, our findings indicate that while the global incidence of infertility related to TS is generally declining in most regions, there is a notable increase in the burden of infertility due to TS in middle SDI areas. This trend may suggest that for developing countries, the capacity for early diagnosis is crucial for the management of girls with TS. 38 However, notably, numerous data gaps persist in environments with limited resources. 39 This may also account for the virtually unchanged prevalence rates observed in low and lower-middle SDI countries. It is noteworthy that the burden of infertility linked to TS is primarily concentrated in Europe and the United States. A recent research report underscores that countries with higher ASPRs for TS are similarly clustered in North America and Europe. This could be due to the advanced healthcare systems in these regions, which are more likely to identify cases of TS. 28 As for KS, Europe also bears a significant brunt of infertility associated with this condition. It is noteworthy that in 2021, the European Society of Endocrinology established the first guidelines on KS, offering recommendations tailored to cater to KS patients across various developmental stages, ranging from childhood and adolescence to adulthood. 32 Early intervention is vital for preserving fertility in patients with KS and TS, highlighting the necessity of enhanced early screening. Yet, underdiagnosis is prevalent in KS, with only around a quarter of patients diagnosed in their lifetime. 40 High-income countries, equipped with advanced diagnostic technologies, can comprehensively identify cases. If undiagnosed prenatally, the condition is rarely identified within the first decade of life, with 75% of cases remaining undiagnosed indefinitely. 41 Currently, karyotype analysis remains the gold standard for prenatal diagnosis, 19 while non-invasive prenatal testing (NIPT) serves as a non-invasive screening alternative. Cell-free fetal DNA, isolated from maternal peripheral blood, forms the analytical basis of NIPT. 42 While the use of NIPT for sex chromosome aneuploidy detection remains controversial, a recent large-scale retrospective study demonstrated that NIPT-based SCA screening has significantly increased population-level prenatal diagnosis rates, particularly for KS. 43 Meanwhile, the rapid growth in middle-income countries highlights the need to balance healthcare advancement with disease prevention. Apart from establishing a tiered screening and diagnosis pathway, family support plays a vital role in holistic KS and TS management, from screening to treatment. 44 Given the current focus on multidisciplinary care, strengthening genetic counseling services is urgently needed. 45 Particularly, low-income countries necessitate the widespread adoption of low-cost screening strategies. QF-PCR is a widely adopted prenatal diagnostic method for detecting common chromosomal abnormalities in recent years. It enables rapid diagnosis of common aneuploidies within hours post-sampling, featuring high throughput, low error rates, and cost-effectiveness. 46 A study proposes a possible cost-effective prenatal diagnosis strategy for low-SDI countries: initial rapid QF-PCR screening for common aneuploidies, followed by targeted chromosomal microarray analysis when indicated. 47 This study is based on the authoritative GBD 2021 database, systematically analyzing data from 204 countries/regions from 1990 to 2021, enhancing the universality and comparability of the results. It comprehensively reveals the global burden differences of KS and TS on infertility across multiple dimensions, including gender (male/female infertility), age (grouped by 15–49 years), region (stratified by SDI), and economic development level (high/medium/low SDI), providing key evidence-based insights for reproductive medicine and public health policies. But a limitation of this study is that the true prevalence and YLDs in low-SDI regions may not be fully captured due to inadequate screening methods. Additionally, factors such as environmental exposures, cultural practices related to childbirth, and racial differences were not accounted for, which could provide new perspectives for studying infertility caused by sex chromosome disorders. As GBD estimates are model-derived, their accuracy is inherently limited by data completeness and diagnostic practices that differ widely across countries; in many low- and middle-income settings the absence of cytogenetic confirmation likely leads to under-estimation of true prevalence.

From 1990 to 2021, male infertility attributable to Klinefelter syndrome rose steadily, whereas female infertility linked to Turner syndrome declined slightly. This divergence underscores the urgent need for effective prepubertal detection, fertility-preservation counselling, and targeted screening in Europe, East Asia and North America. In low-SDI regions, priority should be given to establishing low-cost screening strategies that secure equitable first-step care for individuals with KS or TS.