{"paper_id":"e44ac70c-0a78-4695-b9d1-869d30c96a5b","body_text":"The association between HPV infection and endometriosis: Risk and fertility outcomes\nWenqu Li, Zhenlong Wang, Huizhi Qi, Chengjie Xia, Feixue Chen, Juan Xu, Lei Zhang, Xuemei Jia\nCite this article as:\nWenqu Li, Zhenlong Wang, Huizhi Qi, Chengjie Xia, Feixue Chen, Juan Xu, Lei Zhang, Xuemei Jia. The association between HPV\ninfection and endometriosis: Risk and fertility outcomes[J]. 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China.\nAbstract\nWhile infections have been implicated in endometriosis pathogenesis, the role of human papillomavirus (HPV)\nremains  unclear.  This  study  combined  a  meta-analysis  of  seven  studies  with  a  case-control  study  (n  =  432\nsurgically treated patients) to evaluate the association between HPV and endometriosis risk and fertility outcomes.\nThe  meta-analysis  showed  no  significant  association  between  any  subtypes  of  HPV  (pooled  odds  ratio  [OR]  =\n2.60,  95%  confidence  interval  [CI]:0.28–23.87)  or  high-risk  subtypes  (OR  =  1.68,  95%CI:  0.49–5.75)  infection\nand endometriosis risk, despite a higher HPV prevalence in patients (46% overall, 36% high-risk) compared with\nthe  general  populations.  Limited  data  existed  on  the  association  between  HPV  infection  and  fertility  outcomes\n(two  studies  only).  Our  case-control  analysis  revealed  that  HPV-positive  patients  had  significantly  lower\npostoperative  live  birth  rates,  compared  with  HPV-negative  counterparts  (10.6%  vs.  21.0%,  P  <  0.05).  These\nfindings  suggest  that  HPV  infection  is  not  a  primary  risk  factor  for  endometriosis  development,  but  it  may\nadversely  affect  post-surgical  fertility  outcomes.  The  dual-method  approach  strengthens  the  evidence  for  HPV's\nclinical impact on reproductive prognosis in patients with existing endometriosis.\nKeywords: human  papillomavirus,  endometriosis,  female  infertility,  pregnancy  outcomes,  meta-analysis,  case-\ncontrol analysis.\n \nIntroduction\nDeclining  fertility  is  one  of  the  key  health  issues\naffecting  the  birth  rate.  It  is  crucial  to  investigate  the\nrisk  of  gynecological  disorders  that  affect  female\nfertility,  to  safeguard  women’s  reproductive  health,\npromote  lifelong  well-being,  and  ensure  population\nstability.\nEndometriosis  is  a  benign  gynecological  disorder\ncharacterized  by  the  growth  of  endometrial  tissue\noutside  the  uterus.  It  affects  10%–15%  of  women  of\nreproductive age and is one of the major contributors\nto female infertility. A study from 2008 reported that\napproximately  70.6%  of  women  with  endometriosis\nexperienced  fertility  problems,  with  an  infertility  rate\nof  18.9%[1].  Another  controlled  study  revealed  a\nsixfold  increase  in  the  prevalence  of  infertility  or\nsubfertility  among  endometriosis  patients  compared\n△These authors contributed equally to this work\n✉Corresponding  authors:  Xuemei  Jia  and  Lei  Zhang,  Department\nof Gynecology, Women’s Hospital of Nanjing Medical University,\nNanjing  Women  and  Children's  Healthcare  Hospital,  123  Tianfei\nAlley,  Mochou  Road,  Nanjing,  Jiangsu  210004,  China.  E-mails:\nxmjia@njmu.edu.cn (Jia) and njsfyzl@163.com (Zhang).\nReceived: ;\nCLC number: , Document code: A\nThe authors reported no conflict of interests.\nThis is an open access article under the Creative Commons Attribu-\ntion (CC BY 4.0) license, which permits others to distribute, remix,\nadapt and build upon this work, for commercial use, provided the\noriginal work is properly cited.\n \nAvailable online at www.jbr-pub.org.cn\nOpen Access at PubMed Central\nJournal of Biomedical Research, 2025 39(0): 1–12  \n \nOriginal Article\n©  2025 by Journal of Biomedical Research. https://doi.org/10.7555/JBR.39.20250194\nUnproofed\n\nwith  controls[2].  Women  with  endometriosis  may\nexhibit  abnormal  oocyte  development  and  impaired\nendometrial  receptivity,  making  them  more\nsusceptible  to  infertility,  fatigue,  multisite  pain,  and\nother complications[3]. Despite these findings, the risk\nfactors  influencing  fertility  in  women  with\nendometriosis remain unclear.\nIncreasing  evidence  suggests  a  close  association\nbetween  infections  and  the  onset,  progression,  and\ninfertility  associated  with  endometriosis[4].  For\ninstance,  Fusobacterium  infection  may  promote  the\ndevelopment  of  ovarian  endometriosis[5],  and\neradicating  this  bacterium  could  be  a  potential\ntreatment  for  the  condition.  Additionally,  human\npapillomavirus  (HPV)  infections  originating  in  the\ncervix  can  spread  to  the  endometrium  because  of\nanatomical  proximity,  thereby  increasing  the  risk  of\nendometrial  HPV  infection.  Furthermore,  HPV\ninfections  are  recognized  for  impairing  male  fertility\nby  decreasing  sperm  motility  and  increasing  sperm\nDNA fragmentation[6-7]. However, clinical evidence is\ninsufficient to confirm whether HPV infection affects\nfertility in female patients.\nMeanwhile,  evidence  has  indicated  a  correlation\nbetween  endometriosis  and  HPV  infection,  with  the\nprevalence  of  endometriosis  significantly  higher\namong  HPV(+)  individuals  compared  with  HPV(-)\nindividuals[8]. Additionally, studies have demonstrated\nthat  infertile  women  exhibit  a  greater  likelihood  of\nHPV-related  cervical  cytological  abnormalities[9].\nFurthermore,  female  HPV  infection  reduces  the\nsuccess  rate  of  in  vitro  fertilization[10],  increases  the\nrisk  of  miscarriage  and  leas  to  other  adverse\npregnancy outcomes, such as lower live birth rates[8,11].\nNevertheless,  other  studies  have  found  no\nsignificant  difference  in  the  probability  of  HPV\ninfection  between  women  who  conceived  through  in\nvitro  fertilization  due  to  tubal  or  partner  factors  and\nthose who did not become pregnant[12]. While the HPV\ngenotype  may  influence  fertility  outcomes,  limited\ndata  and  small  sample  sizes  have  impeded  definitive\nconclusions.  Epidemiological  evidence  suggests\nassociations  between  infectious  agents  and\nendometriosis development, between infectious agents\nand  endometriosis-related  infertility,  and  between\nHPV  infection  and  endometriosis;  however,  the\nspecific  impact  of  HPV  infection  on  pregnancy\noutcomes  in  affected  patients  remains  unclear.\nTherefore,  it  is  worth  exploring  whether  HPV\ninfection is associated with adverse fertility outcomes\nin  patients  with  endometriosis.  This  study  aims  to\ninvestigate the correlation between HPV infection and\nthe  incidence  of  endometriosis  and  infertility,\nproviding important evidence for clinical interventions\nin managing endometriosis-related infertility. \nMaterials and Methods\n \nMeta-analysis \nSearch strategy\nThis  review  was  registered  with  PROSPERO\n(CRD420250651884).  We  searched  PubMed,\nEMBASE,  and  Web  of  Science  for  articles  published\nfrom  their  inception  to  September  2024,  without\nrestrictions  on  language  or  publication  status.  The\nsearch algorithm was constructed using the following\nterms  and  adapted  for  each  database:\n((\"Endometriosis\"[Mesh])  OR  (((Endometrioses)  OR\n(Endometrioma))  OR  (Endometrioma)))  AND\n(((((((((((((((Human  Papillomavirus  Virus)  OR\n(Papillomavirus  Virus,  Human))  OR  (Virus,  Human\nPapillomavirus))  OR  (Human  Papilloma  Virus))  OR\n(Human  Papilloma  Viruses))  OR  (Papilloma  Virus,\nHuman)) OR (Virus, Human Papilloma)) OR (Human\nPapillomavirus))  OR  (Human  Papillomaviruses))  OR\n(HPV  Human  Papillomavirus))  OR  (HPV  Human\nPapillomaviruses))  OR  (Human  Papillomaviruses,\nHPV)) OR (Human Papillomavirus, HPV)) OR (HPV,\nHuman  Papillomavirus  Viruses))  OR  (\"Human\nPapillomavirus  Viruses\"[Mesh])).  Additionally,\nreference  lists  of  relevant  articles  were  manually\nreviewed using the snowball method to maximize the\namount of evidence. \nStudy selection and data collection\nWe considered studies eligible for inclusion if they\nwere  case-control,  cross-sectional,  or  cohort  studies.\nThe  study  population  included  women  aged  20–55\nyears, with no restrictions on race, geographic region,\nor sample size. In cases of duplicate publications, the\nversion  with  the  most  comprehensive  data  was\nretained.  Endometriosis  research  was  accepted,\nirrespective  of  the  presence  of  a  control  group.  All\ntypes and locations of endometriosis, along with their\nassociated symptoms, met the inclusion criteria in the\ninitial  search.  The  diagnosis  of  endometriosis  was\nconfirmed  through  laparoscopy  or  self-reported\nquestionnaires, whereas HPV infection was identified\nusing  HPV-DNA  testing  of  reproductive  tract\nsamples,  without  any  restrictions  on  HPV  genotypes.\nAccording  to  their  carcinogenic  potential,  HPV  types\nare  classified  as  high-risk  and  low-risk.  High-risk\nHPV strains include 16, 18, 26, 31, 33, 35, 39, 45, 51,\n52, 53, 56, 58, 59, 66, 68, 73, and 82. Low-risk HPV\nstrains include 3, 6, 11, 30, 34, 35, 40, 42, 43, 44, 54,\n2 Li W et al. J Biomed Res, 2025, 39(0)\nUnproofed\n\n55, 61, 62, 64, 67, 69, 70, 71, 72, 74, 81, 83, 84, 89,\n90, 91, and IS39. Patients infected with both low-risk\nand  high-risk  HPV  were  classified  as  having  a  high-\nrisk  HPV  infection.  Primary  outcomes  evaluated  the\nprevalence  of  HPV  infection  in  women  with\nendometriosis  or  its  association  with  the  disease.\nAdditionally,  to  investigate  the  association  between\nHPV  infection  and  pregnancy  outcomes  in\nendometriosis  patients,  studies  reporting  relevant\npregnancy data were included in the initial search.\nStudies were excluded if they were case series, case\nreports,  of  low  methodological  quality  (as  evaluated\nby  predefined  criteria)  or  lacked  sufficient  data.  Two\ninvestigators  independently  reviewed  the  titles  and\nabstracts,  excluding  irrelevant  content.  Any\ndiscrepancies  were  resolved  through  discussion\namong the authors. \nData item and synthesis\nData  were  extracted  and  recorded  using  a\nstandardized form, which included general information\n(first author, publication year, title, investigation period\nand  region,  and  study  phase),  study  characteristics\n(number  of  participants,  study  design,  and  sampling\nmethods),  participant  characteristics  (age,  sexual\nhistory,  diagnostic  methods  for  endometriosis,  HPV\ndiagnostic  methods  and  typing,  history  of  HPV\nvaccination,  and  presence  of  infertility),  and  study\noutcomes (number of HPV infections in the case group\n[endometriosis  group]  and  control  group  [non-\nendometriosis group] and number of infertility cases in\nthe  endometriosis  group).  The  primary  outcome  was\nthe  influence  of  HPV  infection  on  the  development  of\nendometriosis  and  pregnancy  in  patients  with\nendometriosis,  while  the  secondary  outcome  was  the\nHPV infection rate in the case groups.\nThe statistical measure used to estimate the overall\nprevalence  of  HPV  infection  among  individuals  with\nendometriosis  was  the  infection  rate  within  the  case\ngroup.  To  evaluate  the  association  between  HPV\ninfection and the risk of endometriosis and infertility,\nodds  ratios  (ORs)  were  calculated  to  determine  the\ndifferences  in  HPV  infection  rates  between  the  case\nand  control  groups,  as  well  as  between  the  infertility\ngroup  and  the  normal  pregnancy  group  within  the\nendometriosis population.\nThe  meta-analysis  was  conducted  using  R  software\n(version  4.4.2)  and  the  Meta  package.  Statistical  effect\nmeasures  were  logarithmically  transformed,  and  the\ninverse  variance  method  was  applied.  The  pooled  HPV\nprevalence  in  endometriosis  was  estimated  using  a\nrandom-effects  Poisson-log-normal  model.\nHeterogeneity  among  studies  was  assessed  using\nCochrane’s  Q  test  in  conjunction  with  the  I2  statistic.  A\nfixed-effects model was selected if P > 0.1 and I2 < 50%.\nIf  P  ≤  0.1  and  I2  >  50%,  significant  heterogeneity  was\ndeemed  present,  and  its  sources  were  explored.  Due  to\nthe  limited  number  of  studies  included,  subgroup\nanalysis  and  publication  bias  assessments  were  not\nconducted. The significance level was set at α = 0.05. \nQuality assessment and risk of bias\nIn  the  current  study,  the  quality  of  the  included\nliterature  was  rigorously  assessed,  and  the  items\noutlined  in  the  PRISMA  statement  were  strictly\nfollowed.  Due  to  the  inclusion  of  fewer  than  10\nstudies[13-19],  publication  bias  could  not  be  evaluated\nusing Egger’s test, which limited the statistical power\nof the analysis. The quality assessment of the included\nstudies  was  independently  conducted  by  two\ninvestigators,  with  cross-verification.  In  cases  of\ndisagreement,  a  third  investigator  was  consulted  to\nresolve the discrepancies.\nFor  cross-sectional  studies[16-19],  the  quality  of  the\nresearch  was  assessed  using  the  quality  assessment\nscale  recommended  by  the  Agency  for  Healthcare\nResearch  and  Quality  (AHRQ).  This  scale  comprises\n11 items, each of which is answered with \"yes,\" \"no,\"\nor  \"unclear.\"  The  scores  range  from  zero  to  11,  with\n8–11  stars  indicating  high  quality,  4–7  indicating\nmoderate quality, and 0–3 indicating low quality.\nFor  case-control  studies[13-15],  the  quality  of  the\nstudy was assessed using the Newcastle-Ottawa Scale\n(NOS),  which  evaluates  three  domains:  the  selection\nof  cases  and  controls,  the  comparability  between\nthem,  and  the  assessment  of  exposure.  Scores  range\nfrom zero to 9, with 7–9 stars indicating high quality,\n4–6  indicating  moderate  quality,  and  0–3  indicating\nlow quality. \nCase-control study \nStudy subjects and grouping\nA  case-control  study  was  conducted  to  analyze  the\nclinical  data  of  patients  who  underwent  surgical\ntreatment for endometriosis at Nanjing Maternity and\nChild  Health  Care  Hospital  (also  known  as  the\nWomen’s  Hospital  of  Nanjing  Medical  University)\nbetween January 2017 and June 2022. Based on their\nHPV  infection  status,  patients  were  categorized  into\ntwo groups: the HPV(−) group and the HPV(+) group,\nwhich  included  both  high-risk  and  low-risk  HPV(+)\nsubgroups. \nEthics approval and consent to participate\nThe  current  study  received  approval  from  the\nHPV infection and endometriosis 3\nUnproofed\n\nClinical  Research  Ethics  Committee  of  Nanjing\nMaternity  and  Child  Health  Care  Hospital  (Approval\nNo.  2022KY-100)  and  was  conducted  in  accordance\nwith the Declaration of Helsinki. The study adhered to\nestablished ethical standards. \nInclusion and exclusion criteria\nThe  inclusion  criteria  included:  (1)  Women  of\nreproductive  age  ≤  40  years  at  the  time  of  surgery;\nand  (2)  Diagnosis  of  endometriosis  confirmed  by\npostoperative  pathological  results.  The  exclusion\ncriteria included: (1) Coexisting diseases significantly\nimpairing fertility (e.g., adenomyosis, uterine fibroids,\netc.);  (2)  Concurrent  malignancies  (e.g.,  endometrial\ncancer, cervical cancer, ovarian cancer, etc.); (3) Loss\nto follow-up post-surgery due to personal reasons; and\n(4) Missing clinical data. \nResearch methods\nHPV infection was detected by HPV DNA testing,\nthe WHO-recommended primary test. The patient was\npositioned  in  the  lithotomy  position.  The  cervix  was\nexposed  using  a  speculum,  and  cervical  secretions\nwere  collected  using  an  HPV  sampling  brush.  HPV\nnucleic  acid  detection  and  genotyping  kit  (PCR\ncapillary  electrophoresis  fragment  analysis)  (Health\nGenetech  Co.,  Ltd.,  Guangzhou,  China)  was  used  to\ndetect  HPV  DNA  in  patients'  cervical  secretions,\nincluding high-risk HPV types 16, 18, 26, 31, 33, 35,\n39,  45,  51,  52,  53,  56,  58,  59,  66,  68,  73,  and  82,  as\nwell as low-risk HPV types 6, 11, 42, 43, 44, 81, and\n83  according  to  the  manufacturer's  instructions.  If  a\npatient  was  infected  with  at  least  one  high-risk  HPV\ntype,  she  was  considered  to  be  positive  for  high-risk\nHPV.\nThe  intraoperative  scoring  and  staging  of\nendometriosis  were  performed  based  on  the  revised\nAmerican  Fertility  Society  (rAFS)  classification,\nwherein  points  were  allocated  as  follows:  for\nendometriotic lesions, superficial peritoneal implants <\n1 cm, 1–3 cm, and  > 3 cm received 1, 2, and 4 points,\nrespectively,  while  deep  peritoneal  implants  of\ncorresponding  sizes  received  2,  4,  and  6  points;\nsuperficial  ovarian  implants  <  1  cm,  1–3  cm,  and  >  3\ncm  scored  1,  2,  and  4  points  per  side,  and  deep\novarian  implants  received  4,  16,  and  20  points;\nposterior  cul-de-sac  obliteration  contributed  4  points\nfor  partial  and  40  points  for  complete  closure;\nadhesions  were  scored  based  on  density  and  extent,\nwith thin adhesions scoring 1, 2, or 4 points and dense\nadhesions scoring 4, 8, or 16 points for  < 1/3, 1/3–2/3,\nor  >  2/3  enclosure  of  each  adnexal  structure  (ovaries\nand  fallopian  tubes),  and  complete  enclosure  of  the\nfimbriated  end  automatically  scored  16  points;  the\ntotal score was categorized into stage I (1–5), stage II\n(6–15), stage III (16–40), or stage IV (> 40)[20].\nThe  endometriosis  fertility  index  (EFI)  was\ncalculated  according  to  the  criteria  summarized  and\nrefined  by  Adamson  et  al[21],  which  comprises  two\ncomponents: the total history factor score and the total\nsurgical  factor  score.  The  total  surgical  factor  score\nincludes  both  the  lowest  functioning  (LF)  score  and\nthe r-AFS score. The left and right fallopian tubes and\novaries  are  scored  individually,  and  the  LF  score  is\ndetermined  by  summing  the  lowest  scores  from  each\nside. If one ovary is absent, the LF score is calculated\nas twice the lowest score of the contralateral side.\nPreoperative  cancer  antigen  125  (CA125)\nconcentrations  were  measured  using  the\nchemiluminescent  reagent  kit  (Cat  #  07026986190,\nRoche,  Basel,  Switzerland)  by  a  COBAS  6 000\nanalyzer  (Roche).  Briefly,  after  a  first  12  µL-sample\nincubation  with  biotinylated  and  ruthenium-labeled\nCA125  antibodies  to  form  the  sandwich  complex,\nstreptavidin-coated  microparticles  were  added  in  a\nsecond  step  to  bind  the  complex  via  biotin-\nstreptavidin.  The  microparticles  were  then\nmagnetically  immobilized  on  the  electrode  surface.\nAfter  washing,  the  voltage-stimulated\nchemiluminescence  was  measured.  Results  were\ncalculated  from  an  instrument-specific  two-point\ncalibration curve and the cobas-link master curve. \nStatistical methods\nData  processing  and  statistical  analysis  were\nconducted  using  SPSS  software  version  26.0.\nQuantitative  data  that  were  not  normally  distributed\nwere  presented  as  medians  with  25th  and  75th\npercentiles,  and  intergroup  comparisons  were\nperformed  using  the  non-parametric  test  (Mann-\nWhitney  U  test).  Qualitative  data  were  expressed  as\nfrequencies  and  percentages  (%),  and  group\ncomparisons were analyzed using the Chi-square test.\nFor 2 × 2 contingency tables, Pearson's Chi-square test\nwas used when the minimum expected count was  ≥ 5\nand  the  sample  size  (n)  exceeded  40;  otherwise,\nFisher’s  exact  test  was  used.  A  two-sided  test  with  a\nP-value < 0.05 was considered statistically significant. \nResults\n \nMeta-analysis  of  the  association  between  HPV\ninfection and endometriosis and infertility\nTo  investigate  the  association  between  HPV\ninfection  and  endometriosis  risk  and  infertility,  we\ninitially  searched  for  published  articles  on  HPV\n4 Li W et al. J Biomed Res, 2025, 39(0)\nUnproofed\n\ninfection,  endometriosis,  and  fertility  outcomes  in\npatients  with  endometriosis,  yielding  a  total  of  283\narticles. After removing 80 duplicates, 51 studies were\nscreened  based  on  their  paper  titles,  abstracts,  and\nreliability, and 46 were identified as potentially eligible\nfor  inclusion  and  were  retrieved  in  full  text.  Among\nthese,  39  studies  were  excluded  for  not  meeting  the\ninclusion  criteria,  including  one  without  a  control\ngroup[22] and another with an irrelevant target disease[8].\nSeven  studies  met  the  qualitative  and  quantitative\ncriteria  for  our  meta-analysis[13-19]  (Fig.  1).  However,\nonly  two  articles  explored  the  association  between\nHPV  infection  and  infertility  in  patients  with\nendometriosis.  We  first  conducted  a  meta-analysis  to\nassess  the  association  between  HPV  infection  and\nendometriosis  risk,  between  high-risk  HPV  infection\nand endometriosis risk, and between HPV infection and\ninfertility  in  patients  with  endometriosis.  The  main\ncharacteristics  of  the  included  studies  are  described  in\nTable 1. \n \nRecords identified from\ndatabase searching:\nPubMed, EMBASE, \nWeb of Science (n=283)\nAdditional records \nidentified through other \nsources, manual search \n(n=0)\nTotal records before \nremoval of duplicates \n(n=283)\nDuplicate records \nremoved \n(n=80)\nRecords screened via \ntitle and abstract (n=203)\nRecords excluded due to \nirrelevance (n=157)\nFull-text articles chosen \nas potentially eligible \n(n=46)\nStudies included in \nmeta-analysis (n=7)\nRecord excluded with \nreason: (n=39)\nNon-English (n=1)\nConference abstract (n=2)\nReview (n=34)\nNo control (n=1)\nNon-target disease (n=1)\nIdentificationScreeningIncluded\n \n \nFig.  1     Flow  diagram  of  studies  identified,  included,  and\nexcluded.\n \nTable 1   Characteristics of included studies\nStudy Hong\net al (2023)[17]\nMoslehi\net al (2023)[18]\nOppelt\net al (2010)[13]\nHeidarpour\net al (2017)[16]\nRocha\net al (2019)[15]\nOkyay\net al (2023)[19]\nVestergaard\net al (2010)[14]\nCountry United States Iran Germany Iran Brazil Turkey Denmark\nDesign Cross-sectional Cross-sectional Case-control Cross-sectional Case-control Cross-sectional Case-control\nWith\nendometriosis 129 81 56 50 29 410 32\n　HPV(+) 57 20 14 13 24 202 1\n　HPV(−) 72 61 15 37 5 208 31\n　Not available 0 0 27 0 0 0 0\nWithout\nendometriosis 1 639 – 13 49 31 – 20\n　HPV(+) 765 – 9 5 11 – 2\n　HPV(−) 874 – 0 44 20 – 18\n　Not available 0 – 4 0 0 – 0\nHigh-risk HPV\ntypes\n16, 18, 26, 31, 33,\n35, 39, 45, 51, 52,\n53, 56, 58, 59, 66,\n68, 73, 82\n16, 18, 35, 51,\n52, 53, 68\n16, 18, 31, 33, 35,\n39, 45, 51, 52, 56,\n58, 59, 68\n16, 18, 31, 33, 35,\n39, 45, 52, 56, 58,\n59\n16, 18, 31, 33, 35,\n39, 45, 51, 52, 53,\n56, 58, 59, 66, 68,\n73, 82\n16, 18, 31, 33, 35,\n39, 45, 51, 52, 56,\n58, 59, 66, 68\n68\nLow-risk HPV\ntypes\n6, 11, 40, 42, 54,\n55, 61, 62, 64, 67,\n69, 70, 71, 72, 81,\n83, 84, 89, IS39\n3,6,11,40 6, 11, 42, 43, 44 –\n6, 11, 30, 34, 40,\n42, 43, 44, 54, 55,\n61, 62, 64, 67, 69,\n70, 72, 74, 81, 83,\n84, 91\n– 35, 70, 90\nHPV detection\nmethod\nLinear Array\nHPV Genotyping\nTest\nHPV Direct\nFlow CHIP\nPCR-based\nELISA\nHPV High-risk\nTyping PCR Kit\nSingle-target\nPCR\nCobas 4800\nHPV Test\nPCR using the\ndegenerate FAP\nprimer pair\nDiagnosis\nmethods Questionnaire\nClinical\nsymptoms,\nsurgery, or\nimaging\nSurgery Surgery Surgery Surgery or\nimaging Surgery\nQuality Moderate Moderate Moderate Moderate Moderate Moderate Moderate\nAbbreviation: HPV, human papillomavirus.\nHPV infection and endometriosis 5\nUnproofed\n\nNo  significant  difference  was  observed  in  HPV\ninfection  rates  between  endometriosis  patients  and\ncontrols\nCurrent evidence on overall rates of HPV infection\nin individuals with endometriosis remains limited. Our\nsystematic  review  identified  only  two  comparative\nstudies  evaluating  the  overall  HPV  infection  rates  in\ncontrol  and  endometriosis  patients  and  four  studies\nspecifically  evaluating  the  high-risk  HPV  infection\nrates  in  control  and  endometriosis  patients.  Using\nrandom-effects  meta-analysis  models,  we  found  no\nstatistically  significant  difference  in  either  overall\nHPV  infection  rates  (OR:  2.60,  95%  CI:  0.28–23.87)\nor  high-risk  HPV  infection  rates  (OR:  1.68,  95%  CI:\n0.49–5.75) with respect to endometriosis risk (Fig. 2).\nThese  non-significant  associations  indicate  that\ncurrent  evidence  does  not  sufficiently  support  an\nepidemiological  association  between  HPV  infection\nand endometriosis risk.\n  \nA\nEMS(+) EMS(−)\nEMS(+) EMS(−)\nStudy or Subgroup Events Total Events Total Weight OR (95% CI) OR (95% CI)\nRodrigo et al 2018 24 29 11 31 46.6% 8.73 (2.60, 29.33)\nYun et al 2023 57 129 765 1 639 53.4% 0.90 (0.63, 1.30)\nTotal (95% CI) 158 1 670 100% 2.60 (0.28, 23.87)\nTotal events 81 776\nHeterogeneity: Tau2=2.361 2; Chi2=12.34, df=1 (P=0.000 4); I2=91.9%\nTest for overall effect: Z=0.85 (P=0.397 8)\nB\nStudy or Subgroup Events Total Events Total Weight OR (95% CI) OR (95% CI)\nAnna L.et al 2010 1 32 2 20 14.3% 0.29 (0.02, 3.43)\nMitra et al2016 13 50 5 49 26.5% 3.09 (1.01, 9.48)\nRodrigo et al2018 19 29 7 31 26.4% 6.51(2.09, 20.33)\nYun et al2023 31 129 489 1 639 32.8% 0.74(0.49, 1.13)\nTotal (95% CI) 240 1 739 100.0% 1.68(0.49, 5.75)\nTotal events 64 503\nHeterogeneity: Tau2=1.157 3; Chi2=17.11, df=3 (P=0.000 7); I2=82.5%\nTest for overall effect: Z=0.83(P=0.408 1)\n0.1 0.5 1 2 10\nFavors HPV (+) Favors HPV (−)\nFavors HPV (−)\n0.1 0.5 1 2 10\nFavors HPV (+)\n \n \nFig. 2   The association of HPV infection (A) and high-risk HPV infection (B) with endometriosis. Odds ratios (ORs) with 95%\nconfidence intervals (CIs) were calculated using inverse-variance weighting. The area of each square corresponds to the study-specific\nweight in the meta-analysis. Horizontal lines span the 95% CI range. Solid vertical ticks indicate point estimates. The red squares denote\nstudies with smaller samples (n  < 100), whose wider confidence intervals indicate lower precision. The diamond reflects the pooled estimate\nwith heterogeneity. Studies are labeled by the first author and publication year. Abbreviations: EMS, endometriosis.\n \nRegarding  absolute  prevalence,  our  analysis\nincorporated  three  studies  comprising  239\nendometriosis  patients,  among  whom  101  cases\n(42.3%)  were  HPV(+),  and  six  studies  comprising\n679  endometriosis  patients,  among  whom  280  cases\n(41.2%)  were  infected  with  high-risk  HPV.  The\nrandom-effects  model  estimated  a  pooled  HPV\ninfection  prevalence  of  46%  (95%  CI:  0.23–0.90)\nand  a  pooled  high-risk  HPV  infection  prevalence  of\n36%  (95%  CI:  0.23–0.56)  in  endometriosis  patients\n(Fig. 3). \nConflicting  evidence  on  HPV  infection  and\nendometriosis-associated infertility\nCurrent  research  presents  contradictory  findings\nregarding  the  association  between  HPV  infection  and\ninfertility  in  endometriosis  patients[18-19].  Our  analysis\nidentified  two  studies  with  opposing  conclusions.  A\nrandom-effects  meta-analysis  revealed  no  statistically\nsignificant  difference  in  HPV  infection  rates  between\nthe infertility group of patients with endometriosis and\nthose  with  normal  pregnancies  (OR:  0.73,  95%  CI:\n0.07–7.20)  (Fig.  4).  Considering  the  small  sample\n6 Li W et al. J Biomed Res, 2025, 39(0)\nUnproofed\n\nsizes  in  both  studies,  further  investigation  into  the\nassociation  between  HPV  infection  and  infertility  in\npatients with endometriosis is warranted. \nThe  case-control  analysis  revealed  that  HPV\ninfection was significantly associated with reduced\nlive birth rate among endometriosis patients under\n40 years of age. \nThe postoperative live birth rate was significantly lower\nin the HPV(+) group compared with the HPV(−) group\nTo  further  investigate  the  effects  of  HPV  infection\non  the  fertility  of  women  with  endometriosis,  we\nconducted a case-control study. A total of 432 patients\nwith  endometriosis  were  included  in  the  study,  of\nwhom  66  were  infected  with  HPV  before  surgery.\nThis group comprised 49 patients with high-risk HPV\ninfections  (including  10  patients  with  HPV  types  16\nand  18,  four  of  whom  had  mixed  infections),  13\npatients  with  low-risk  HPV  infections,  and  four\npatients  with  both  high-risk  and  low-risk  HPV\ninfections.  The  remaining  366  patients  were  in  the\nHPV(−) group. Baseline characteristics, including age,\n \nStudy or Subgroup Events Total Weight Proportion (95%CI)\nZohreh et al 2023 20 81 31.6% 0.25 (0.16, 0.36)\nRodrigo et al 2018 24 29 34.3% 0.83 (0.64, 0.94)\nYun et al 2023 57 129 34.1% 0.44 (0.35, 0.53)\nTotal (95% CI) 239 100% 0.46 (0.23, 0.90)\nTotal events 101\nHeterogeneity: Tau2=0.340 4; Chi2=44.51, df=2 (P<0.000 1); I2=95.5%  \nStudy or Subgroup Events Total Weight Proportion(95%CI)\nPeter et al 2010 14 29 18.4% 0.48(0.29, 0.67)\nRodrigo et al 2018 19 29 19.8% 0.66(0.46, 0.82)\nMitra et al 2016 13 50 17.2% 0.26(0.15, 0.40)\nEmre et al 2023 202 410 21.1% 0.49(0.44, 0.54)\nAnna L.et al 2010 1 32 4.2% 0.03 (0.00, 0.16)\nYun et al 2023 31 129 19.3% 0.24 (0.17, 0.32)\nTotal (95% CI) 679 100% 0.36(0.23, 0.56)\nTotal events 280\nHeterogeneity: Tau2=0.235 5; Chi2=39.07, df=5 (P<0.000 1); I2=87.2%\n0.2 0.4 0.6 0.8\n0.2 0.4 0.8 1.0\nA\nB\n \n \nFig. 3   Forest plot analysis comparing prevalence rates of any HPV infection (A) versus high-risk HPV subtypes (B) among women\nwith endometriosis.  Proportions  with  95%  confidence  intervals  (CIs)  were  calculated  using  a  random-effects  Poisson-log-normal  model.\nThe area of each square corresponds to the study-specific weight in the meta-analysis. Horizontal lines span the 95% CI range. Solid vertical\nticks  indicate  point  estimates.  The  red  squares  denote  studies  with  smaller  samples  (n  <  100),  whose  wider  confidence  intervals  indicate\nlower precision. The diamond reflects the pooled estimate with heterogeneity. Studies are labeled by the first author and publication year.\n \nInfertility (+) Infertility (−)\nStudy or Subgroup Events Total Events Total Weight OR (95% CI) OR (95% CI)\nZohreh et al 2023 3 31 17 50 46.8% 0.21 [0.06, 0.78]\nEmre et al 2023 31 47 171 363 53.2% 2.18 [1.15, 4.12]\nTotal (95% CI) 100% 0.73 [0.07, 7.20]\nTotal events 34 188\nHeterogeneity: Tau2=2.473 4; Chi2=9.77, df=1 (P=0.001 8); I2=89.8%\nTest for overall effect: Z=−0.27 (P=0.783 7)\n0.1 0.5 1 2 10\nFavors HPV (+) Favors HPV (−)\n \n \nFig. 4   HPV infection and infertility risk in endometriosis: a random-effects meta-analysis of two cross-sectional studies. Odds ratios\n(ORs)  with  95%  confidence  intervals  (CIs)  were  calculated  using  inverse-variance  weighting.  The  area  of  each  square  corresponds  to  the\nstudy-specific  weight  in  the  meta-analysis.  Horizontal  lines  span  the  95%  CI  range.  Solid  vertical  ticks  indicate  point  estimates.  The  red\nsquares denote studies with smaller samples (n  < 100), whose wider confidence intervals indicate lower precision. The diamond reflects the\npooled estimate with heterogeneity. Studies are labeled by the first author and publication year. IV: inverse variance.\nHPV infection and endometriosis 7\nUnproofed\n\nendometriosis score, EFI, CA125 levels, unilateral and\nbilateral  disease,  and  endometriosis  stage,  were\ncompared  between  the  two  groups.  No  statistically\nsignificant  differences  were  found  (P  >  0.05  for  all)\n(Table 2).\nHowever,  the  postoperative  pregnancy  rate  was\nlower  in  the  HPV(+)  group  compared  with  the\nHPV(−)  group  (15.2%  vs.  24.3%),  and  the  infertility\nclinic visit rate was higher in the HPV(+) group than\nin  the  HPV(−)  group  (18.2%  vs.  14.2%)  ,  although\nthese  differences  did  not  reach  statistical  significance\n(P  =  0.103  and  P  =  0.403,  respectively).  In  contrast,\nthe  postoperative  live  birth  rate  was  significantly\nlower in the HPV(+) group than in the HPV(−) group\n(10.6% vs. 21.0%; P = 0.049) (Table 2). \nNo  significant  differences  were  observed  in\npostoperative  live  birth  rates  between  endometriosis\npatients with low-risk and high-risk HPV infections\nSubgroup  analysis  of  endometriosis  patients  with\nlow-risk  (13  patients)  and  high-risk  HPV  infections\n(53 patients) revealed that the postoperative live birth\nrate  was  higher  in  the  low-risk  group  (15.4%  vs.\n9.4%).  However,  this  difference  was  not  statistically\nsignificant (P > 0.05) (Table 3). \nAmong  endometriosis  patients  achieving\npostoperative  pregnancy,  those  with  high-risk  HPV\ncoinfection  demonstrated  a  24.3% reduction  in  live\nbirth rates compared with HPV(−) or low-risk HPV-\ninfected counterparts\nA  further  analysis  of  pregnancy  outcomes  in\nendometriosis  patients  with  successful  postoperative\npregnancies revealed that the live birth rate was lower\nin those with high-risk HPV infection compared with\npatients  with  no  HPV  infection  or  low-risk  HPV\ninfection (62.5% vs. 86.8%). However, the difference\nwas not statistically significant (P = 0.099) (Table 4). \nDiscussion\nIt  has  been  suggested  that  HPV  infection  may\ninfluence  the  development  of  endometriosis[8].  HPV\ninfection  has  been  detected  in  both  the  upper  and\nlower genital tracts of infertile patients and those with\nendometriosis[15].  Notably,  two  studies  that  detected\nHPV  infection  within  endometriosis  lesions  indicated\nthat HPV might ascend through the genital tract to the\nuterine  cavity,  potentially  contributing  to  the\ndevelopment  of  endometriosis[13-14].  However,  the\n \nTable 2   Association of HPV coinfection with clinicopathological features and fertility outcomes in endometriosis patients\nVariable HPV(+) group (n=66) HPV(−) group (n=366) P value\nAge [years, median (Q1, Q3)] 32 (30.0, 36.0) 31 (28.0, 36.0) 0.360a\nEndometriosis scoring [points, median (Q1, Q3)] 40 (32.0, 73.0) 40 (28.0, 73.0) 0.526a\nEFI [points, median (Q1, Q3)] 8.0 (7.0, 9.0) 8 .0(7.0, 9.0) 0.569a\nCA125 [U/ml, median (Q1, Q3)] 50.68 (32.8, 77.6) 46.72 (29.9, 77.2) 0.795a\nAffected area [n (%)]\n　One 44 (66.7%) 241 (65.8%)\n0.897b\n　Both 22 (33.3%) 125 (34.2%)\nEndometriosis staging [n (%)]\n　Stage 3 36 (54.5%) 181 (49.5%)\n0.446b\n　Stage 4 30 (45.5%) 185 (50.5%)\nInfertility clinic visit [n (%)]\n　Yes 12 (18.2%) 52 (14.2%)\n0.403b\n　No 54 (81.8%) 314 (85.8%)\nPostoperative pregnancy [n (%)]\n　Yes 10 (15.2%) 89 (24.3%)\n0.103b\n　No 56 (84.8%) 277 (75.7%)\nPostoperative birth [n (%)]\n　Yes 7 (10.6%) 77 (21.0%)\n0.049b\n　No 59 (89.4%) 289 (79.0%)\nData are presented as median (Q1, Q3) or n (%). Statistical method: aMann-Whitney U test, bChi-square test, cFisher’s exact test. Abbreviation: CA125, cancer antigen\n125; EFI, endometriosis fertility index; HPV, human papillomavirus.\n8 Li W et al. J Biomed Res, 2025, 39(0)\nUnproofed\n\nresults  of  our  meta-analysis  revealed  no  significant\nassociation  between  HPV  infection  (including  high-\nrisk HPV) and endometriosis risk. Further analysis of\nthe prevalence of HPV infection among patients with\nendometriosis,  based  on  seven  studies,  indicated  that\nthe  overall  prevalence  of  HPV  infection  in  patients\nwith  endometriosis  was  46%,  with  a  36%  prevalence\nof high-risk HPV infection. While the reported overall\nHPV  infection  rate  in  women  ranges  from  11.5%  to\n13.1%,  with  high-risk  HPV  infection  rates  varying\nbetween  9.67%  and  24.1%[23-27],  these  data  suggest\nthat  HPV  infection  may  be  more  prevalent  among\npatients  with  endometriosis,  which  is  consistent  with\nthe  findings  of  Heidarpour  et  al[16].  Nevertheless,\nsignificant  heterogeneity  among  studies  and  the\nlimited  number  of  included  investigations  may\nintroduce  potential  bias  and  reduce  statistical  power,\nhighlighting the need for large-scale research to better\nelucidate  both  the  prevalence  of  HPV  infection  in\nendometriosis patients and its potential etiological role\nin disease development.\nIn  patients  with  ovarian-type  endometriosis,  large\novarian  chocolate  cysts  can  compress  the  ovarian\ncortex, leading to atrophy and reduced ovarian reserve\nfunction[28]. The current standard surgical approach for\nendometriosis  involves  removing  as  much  of  the\n \nTable  3   Differential  effects  of  high-risk  HPV  and  low-risk  HPV  infection  on  clinicopathology  and  fertility  in  women  with\nendometriosis and concurrent HPV infection\nVariable Low-risk HPV group (n=13) High-risk HPV group (n=53) P value\nAge [years, median (Q1, Q3)] 33 (30.5, 36.5) 32 (29.5, 36.0) 0.571a\nEndometriosis Scoring [points, median (Q1, Q3)] 36 (28.0, 84.0) 40 (32.0, 70.0) 0.577a\nEFI [points, median (Q1, Q3)] 8.0 (6.5, 8.0) 8.0 (7.0, 9.0) 0.173a\nCA125 [U/ml, median (Q1, Q3)] 36.04 (20.8, 70.8) 50.77 (34.1, 82.0 ) 0.249a\nAffected area [n (%)]\n　One 10 (76.9%) 34 (64.2%)\n0.518c\n　Both 3 (23.1%) 19 (35.8%)\nEndometriosis staging [n (%)]\n　Stage 3 8 (61.5%) 28 (52.8%)\n0.572b\n　Stage 4 5 (38.5%) 25 (47.2%)\nInfertility clinic visit [n (%)]\n　Yes 3 (23.1%) 9 (17.0%)\n0.691c\n　No 10 (76.9%) 44 (83.0%)\nPostoperative pregnancy [n (%)]\n　Yes 2 (15.4%) 8 (15.1%)\n1.000c\n　No 11 (84.6%) 45 (84.9%)\nPostoperative live birth [n (%)]\n　Yes 2 (15.4%) 5 (9.4%)\n0.617c\n　No 11 (84.6%) 48 (90.6%)\nData are presented as median (Q1, Q3) or n (%). Statistical method: aMann-Whitney U test, bChi-square test, cFisher’s exact test,. Abbreviation: CA125, cancer antigen\n125; EFI, endometriosis fertility index; HPV, human papillomavirus.\n \nTable 4   Effect of high-risk HPV infection on post-surgical live birth outcomes in endometriosis patients achieving pregnancy\nVariable\nHPV(−) and low-risk\nHPV infection group\n(n=91)\nHigh-risk HPV\ninfection group\n(n=8)\nP value\nPostoperative live birth [n (%)]\n　Yes 79 (86.8%) 5 (62.5%) 0.099\n　No 12 (13.2%) 3 (37.5%)\nData are presented as n (%). Fisher’s exact test was used. Abbreviation: HPV, human papillomavirus.\nHPV infection and endometriosis 9\nUnproofed\n\nectopic  tissue  as  possible,  but  this  may  result  in\nadverse outcomes, such as impaired ovarian function,\npelvic  adhesions,  and  laparoscopic  surgical\ncomplications,  all  of  which  can  affect  postoperative\npregnancy  outcomes.  Endometriosis  can  result  in  the\naccumulation  of  various  toxic  cytokines  (e.g.,\ninflammatory  cytokines  and  active  macrophages)  in\nthe peritoneal fluid and uterus, which induce a chronic\ninflammatory  response  in  the  pelvic  cavity[29].  This\nchronic  inflammation  can  contribute  to  infertility  and\nmiscarriage. Additionally, HPV infection may further\ntrigger an immune response or increase the production\nof  proinflammatory  cytokines[30-32],  potentially\ncontributing to infertility and pregnancy loss.\nNonetheless,  limited  research  exists  on  the  impact\nof  HPV  infection  on  pregnancy  rates  and  fertility  in\npatients  with  endometriosis.  The  only  two  studies  on\nthe  association  between  HPV  infection  and  infertility\nin  endometriosis  have  reached  conflicting\nconclusions[18-19].  Key  factors  contributing  to  these\ndifferences  include  sample  size  (410  vs.  81),  HPV\nsampling  location  (cervical  scrapings  vs.  both  the\nexocervix  and  tissue  samples),  HPV  testing  methods\n(Cobas 4 800 HPV Test vs. HPV Direct Flow CHIP),\nand confounding variables such as patient age (30–65\nyears vs. 20–50 years), country (Turkey vs. Iran), and\nthe  types  of  HPV  infections  in  the  study  populations\n(14  high-risk  HPVs  vs.  six  high-risk  HPVs  and  five\nlow-risk  HPVs,  with  HPV  types  6  and  11  being  the\nmost  prevalent  in  endometriosis  patients).  For\nexample, Okyay et al[19] included only high-risk HPV\ntypes  in  their  study  and  concluded  that  the  infertility\nrate was significantly higher in the HPV16/18-infected\ngroup.  In  contrast,  Moslehi  et al[18]  included  11  HPV\ntypes in their study (six of which were high-risk HPV\ninfections),  with  fewer  than  60%  of  infections\ninvolved  high-risk  HPV  types,  yet  the  infertility  rate\nin  the  HPV-infected  group  was  significantly  lower\nthan  that  in  the  control  group.  Considering  these\ndiscrepancies,  we  further  analyzed  the  association\nbetween HPV infection and infertility in patients with\nendometriosis in our sample.\nBecause  several  studies  included  in  our  meta-\nanalysis  classified  high-risk  HPV  according  to  the\nIARC  classification  (14  definitive  carcinogenic  types\nin  group  1  and  four  possibly  carcinogenic  types  in\ngroup  2B),  our  case-control  study  adopted  the  same\ncriteria. Using this definition, we found the following\nprevalence  rates:  high-risk  HPV  in  49/66  (74.2%),\nlow-risk  HPV  in  13/66  (19.7%),  and  high-risk/low-\nrisk  co-infections  in  4/66  (6.1%).  The  postoperative\nlive  birth  rate  was  significantly  lower  in  the  HPV(+)\ngroup  than  in  the  HPV(-)  group.  Stratified  analysis\nfurther  showed  a  higher  postoperative  liver  birth  rate\nin  the  low-risk  HPV  infection  group  compared  with\nthe  high-risk  HPV  infection.  These  findings\nsignificantly differ from those reported by Moslehi et\nal,  but  are  more  closely  aligned  with  the  research\nconducted by Okyay et al[18-19], supporting a potential\nassociation  between  high-risk  HPV  infection  and\nworse  fertility  outcomes  in  patients  with\nendometriosis.  This  observation  is  also  in  line  with\nour  subgroup  analysis,  which  indicated  a  lower\npostoperative  live  birth  rate  in  the  high-risk  HPV\ngroup  compared  with  the  low-risk  HPV  infection\ngroup  (9.4%  vs.  15.4%).  Nevertheless,  the  limited\nsample size in our study reduced the statistical power\nof  our  findings.  Further  investigations  are  warranted\nto  elucidate  the  distinct  effects  of  low-risk  versus\nhigh-risk  HPV  infections  on  the  infertility  of\nendometriosis patients.\nHigh-risk  HPV  infection  appears  to  exert  a\nmeasurable  influence  on  reproductive  outcomes.\nHowever,  current  studies,  including  our  own,  are\nlimited  by  relatively  small  sample  sizes  and  low\nstatistical  power.  Furthermore,  the  results  may  have\nbeen  influenced  by  various  confounding  factors,\nincluding  the  HPV  detection  methods,  definitions  of\nhigh-risk HPV, regional variations in HPV genotypes,\nsocioeconomic  status  (particularly  quality  of  life  and\nmarital status), timing of viral exposure, patients’ age,\nand  the  ongoing  fertility  intentions  of  both  patients\nand  their  family  members.  These  variables  likely\nimpact  both  pregnancy  rates  and  overall  fertility\noutcomes,  thereby  introducing  additional  complexity\nto the interpretation of our findings.\nWhile  our  meta-analysis  demonstrated  no\netiological  association  between  HPV  infection  and\nendometriosis  development,  the  case-control  study\nrevealed significantly reduced postoperative live birth\nrates  among  HPV-positive  endometriosis  patients\ncompared  with  their  HPV-negative  counterparts.\nFurthermore,  the  subgroup  analysis  showed  that  the\npostoperative live-birth rate was higher in the low-risk\nHPV  group  than  in  the  high-risk  HPV  group.  These\nfindings  indicate  that  systematically  evaluating  and\nmanaging  concurrent  HPV  infection  in  patients  with\nendometriosis  may  protect  fertility  and  improve\nreproductive  outcomes,  offering  new  intervention\ndirections  for  patients  with  both  endometriosis  and\nHPV infection-related infertility. However, the limited\nsample size in our study reduced the statistical power\nof  these  findings.  Therefore,  future  prospective  and\nlongitudinal  studies  with  larger  sample  sizes  and\ncomprehensive HPV-genotype analyses are warranted\nto validate these findings. \n10 Li W et al. J Biomed Res, 2025, 39(0)\nUnproofed\n\nFunding\nThis  work  was  supported  by  the  National  Natural\nScience Foundation of China (Grant Nos. 82472707 to\nX.J.  and  81901456  to  W.L.),  Jiangsu  Province\nCapability  Improvement  Project  through  Science,\nTechnology,  and  Education,  Jiangsu  Provincial\nMedical  Key  Discipline  (Grant  No.  ZDXK202211  to\nX.J.),  and  Jiangsu  Province  Graduate  Practical\nInnovation  Program  (Grant  No.  SJCX24_0759  to\nZ.W.). \nAcknowledgment\nNone. \nData availability statement\nThe  datasets  generated  or  analyzed  during  the\ncurrent  study  are  not  publicly  available  as  they  form\npart  of  an  ongoing  investigation,  but  are  available\nfrom  the  corresponding  author  upon  reasonable\nrequest.\nReferences\n Flores I, Abreu S, Abac S, et al. Self-reported prevalence of\nendometriosis  and  its  symptoms  among  Puerto  Rican\nwomen[J]. Int J Gynaecol Obstet, 2008, 100(3): 257–261.\n[1]\n Ballard  KD,  Seaman  HE,  de 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J Biomed Res, 2025, 39(0)\nUnproofed","source_license":"CC-BY-4.0","license_restricted":false}