The association between HPV infection and endometriosis: Risk and fertility outcomes

While infections have been implicated in endometriosis pathogenesis, the role of human papillomavirus (HPV) remains  unclear.  This  study  combined  a  meta-analysis  of  seven  studies  with  a  case-control  study  (n  =  432 surgically treated patients) to evaluate the association between HPV and endometriosis risk and fertility outcomes. The  meta-analysis  showed  no  significant  association  between  any  subtypes  of  HPV  (pooled  odds  ratio  [OR]  = 2.60,  95%  confidence  interval  [CI]:0.28–23.87)  or  high-risk  subtypes  (OR  =  1.68,  95%CI:  0.49–5.75)  infection and endometriosis risk, despite a higher HPV prevalence in patients (46% overall, 36% high-risk) compared with the  general  populations.  Limited  data  existed  on  the  association  between  HPV  infection  and  fertility  outcomes (two  studies  only).  Our  case-control  analysis  revealed  that  HPV-positive  patients  had  significantly  lower postoperative  live  birth  rates,  compared  with  HPV-negative  counterparts  (10.6%  vs.  21.0%,  P  <  0.05).  These findings  suggest  that  HPV  infection  is  not  a  primary  risk  factor  for  endometriosis  development,  but  it  may adversely  affect  post-surgical  fertility  outcomes.  The  dual-method  approach  strengthens  the  evidence  for  HPV's clinical impact on reproductive prognosis in patients with existing endometriosis.

human  papillomavirus,  endometriosis,  female  infertility,  pregnancy  outcomes,  meta-analysis,  case- control analysis.

Declining  fertility  is  one  of  the  key  health  issues affecting  the  birth  rate.  It  is  crucial  to  investigate  the risk  of  gynecological  disorders  that  affect  female fertility,  to  safeguard  women’s  reproductive  health, promote  lifelong  well-being,  and  ensure  population stability. Endometriosis  is  a  benign  gynecological  disorder characterized  by  the  growth  of  endometrial  tissue outside  the  uterus.  It  affects  10%–15%  of  women  of reproductive age and is one of the major contributors to female infertility. A study from 2008 reported that approximately  70.6%  of  women  with  endometriosis experienced  fertility  problems,  with  an  infertility  rate of  18.9%[1].  Another  controlled  study  revealed  a sixfold  increase  in  the  prevalence  of  infertility  or subfertility  among  endometriosis  patients  compared △These authors contributed equally to this work ✉Corresponding  authors:  Xuemei  Jia  and  Lei  Zhang,  Department of Gynecology, Women’s Hospital of Nanjing Medical University, Nanjing  Women  and  Children's  Healthcare  Hospital,  123  Tianfei Alley,  Mochou  Road,  Nanjing,  Jiangsu  210004,  China.  E-mails: [email protected] (Jia) and [email protected] (Zhang). Received: ; CLC number: , Document code: A The authors reported no conflict of interests. This is an open access article under the Creative Commons Attribu- tion (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. Available online at www.jbr-pub.org.cn Open Access at PubMed Central Journal of Biomedical Research, 2025 39(0): 1–12 Original Article © 2025 by Journal of Biomedical Research. https://doi.org/10.7555/JBR.39.20250194 Unproofed with  controls[2].  Women  with  endometriosis  may exhibit  abnormal  oocyte  development  and  impaired endometrial  receptivity,  making  them  more susceptible  to  infertility,  fatigue,  multisite  pain,  and other complications[3]. Despite these findings, the risk factors  influencing  fertility  in  women  with endometriosis remain unclear. Increasing  evidence  suggests  a  close  association between  infections  and  the  onset,  progression,  and infertility  associated  with  endometriosis[4].  For instance,  Fusobacterium  infection  may  promote  the development  of  ovarian  endometriosis[5],  and eradicating  this  bacterium  could  be  a  potential treatment  for  the  condition.  Additionally,  human papillomavirus  (HPV)  infections  originating  in  the cervix  can  spread  to  the  endometrium  because  of anatomical  proximity,  thereby  increasing  the  risk  of endometrial  HPV  infection.  Furthermore,  HPV infections  are  recognized  for  impairing  male  fertility by  decreasing  sperm  motility  and  increasing  sperm DNA fragmentation[6-7]. However, clinical evidence is insufficient to confirm whether HPV infection affects fertility in female patients. Meanwhile,  evidence  has  indicated  a  correlation between  endometriosis  and  HPV  infection,  with  the prevalence  of  endometriosis  significantly  higher among  HPV(+)  individuals  compared  with  HPV(-) individuals[8]. Additionally, studies have demonstrated that  infertile  women  exhibit  a  greater  likelihood  of HPV-related  cervical  cytological  abnormalities[9]. Furthermore,  female  HPV  infection  reduces  the success  rate  of  in vitro  fertilization[10],  increases  the risk  of  miscarriage  and  leas  to  other  adverse pregnancy outcomes, such as lower live birth rates[8,11]. Nevertheless,  other  studies  have  found  no significant  difference  in  the  probability  of  HPV infection  between  women  who  conceived  through  in vitro  fertilization  due  to  tubal  or  partner  factors  and those who did not become pregnant[12]. While the HPV genotype  may  influence  fertility  outcomes,  limited data  and  small  sample  sizes  have  impeded  definitive conclusions.  Epidemiological  evidence  suggests associations  between  infectious  agents  and endometriosis development, between infectious agents and  endometriosis-related  infertility,  and  between HPV  infection  and  endometriosis;  however,  the specific  impact  of  HPV  infection  on  pregnancy outcomes  in  affected  patients  remains  unclear. Therefore,  it  is  worth  exploring  whether  HPV infection is associated with adverse fertility outcomes in  patients  with  endometriosis.  This  study  aims  to investigate the correlation between HPV infection and the  incidence  of  endometriosis  and  infertility, providing important evidence for clinical interventions in managing endometriosis-related infertility.

Meta-analysis  Search strategy This  review  was  registered  with  PROSPERO (CRD420250651884).  We  searched  PubMed, EMBASE,  and  Web  of  Science  for  articles  published from  their  inception  to  September  2024,  without restrictions  on  language  or  publication  status.  The search algorithm was constructed using the following terms  and  adapted  for  each  database: (("Endometriosis"[Mesh])  OR  (((Endometrioses)  OR (Endometrioma))  OR  (Endometrioma)))  AND (((((((((((((((Human  Papillomavirus  Virus)  OR (Papillomavirus  Virus,  Human))  OR  (Virus,  Human Papillomavirus))  OR  (Human  Papilloma  Virus))  OR (Human  Papilloma  Viruses))  OR  (Papilloma  Virus, Human)) OR (Virus, Human Papilloma)) OR (Human Papillomavirus))  OR  (Human  Papillomaviruses))  OR (HPV  Human  Papillomavirus))  OR  (HPV  Human Papillomaviruses))  OR  (Human  Papillomaviruses, HPV)) OR (Human Papillomavirus, HPV)) OR (HPV, Human  Papillomavirus  Viruses))  OR  ("Human Papillomavirus  Viruses"[Mesh])).  Additionally,

lists  of  relevant  articles  were  manually reviewed using the snowball method to maximize the amount of evidence.  Study selection and data collection We considered studies eligible for inclusion if they were  case-control,  cross-sectional,  or  cohort  studies. The  study  population  included  women  aged  20–55 years, with no restrictions on race, geographic region, or sample size. In cases of duplicate publications, the version  with  the  most  comprehensive  data  was retained.  Endometriosis  research  was  accepted, irrespective  of  the  presence  of  a  control  group.  All types and locations of endometriosis, along with their associated symptoms, met the inclusion criteria in the initial  search.  The  diagnosis  of  endometriosis  was confirmed  through  laparoscopy  or  self-reported questionnaires, whereas HPV infection was identified using  HPV-DNA  testing  of  reproductive  tract samples,  without  any  restrictions  on  HPV  genotypes. According  to  their  carcinogenic  potential,  HPV  types are  classified  as  high-risk  and  low-risk.  High-risk HPV strains include 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82. Low-risk HPV strains include 3, 6, 11, 30, 34, 35, 40, 42, 43, 44, 54, 2 Li W et al. J Biomed Res, 2025, 39(0) Unproofed 55, 61, 62, 64, 67, 69, 70, 71, 72, 74, 81, 83, 84, 89, 90, 91, and IS39. Patients infected with both low-risk and  high-risk  HPV  were  classified  as  having  a  high- risk  HPV  infection.  Primary  outcomes  evaluated  the prevalence  of  HPV  infection  in  women  with endometriosis  or  its  association  with  the  disease. Additionally,  to  investigate  the  association  between HPV  infection  and  pregnancy  outcomes  in endometriosis  patients,  studies  reporting  relevant pregnancy data were included in the initial search. Studies were excluded if they were case series, case reports,  of  low  methodological  quality  (as  evaluated by  predefined  criteria)  or  lacked  sufficient  data.  Two investigators  independently  reviewed  the  titles  and abstracts,  excluding  irrelevant  content.  Any discrepancies  were  resolved  through  discussion among the authors.  Data item and synthesis Data  were  extracted  and  recorded  using  a standardized form, which included general information (first author, publication year, title, investigation period and  region,  and  study  phase),  study  characteristics (number  of  participants,  study  design,  and  sampling methods),  participant  characteristics  (age,  sexual history,  diagnostic  methods  for  endometriosis,  HPV diagnostic  methods  and  typing,  history  of  HPV vaccination,  and  presence  of  infertility),  and  study outcomes (number of HPV infections in the case group [endometriosis  group]  and  control  group  [non- endometriosis group] and number of infertility cases in the  endometriosis  group).  The  primary  outcome  was the  influence  of  HPV  infection  on  the  development  of endometriosis  and  pregnancy  in  patients  with endometriosis,  while  the  secondary  outcome  was  the HPV infection rate in the case groups. The statistical measure used to estimate the overall prevalence  of  HPV  infection  among  individuals  with endometriosis  was  the  infection  rate  within  the  case group.  To  evaluate  the  association  between  HPV infection and the risk of endometriosis and infertility, odds  ratios  (ORs)  were  calculated  to  determine  the differences  in  HPV  infection  rates  between  the  case and  control  groups,  as  well  as  between  the  infertility group  and  the  normal  pregnancy  group  within  the endometriosis population. The  meta-analysis  was  conducted  using  R  software (version  4.4.2)  and  the  Meta  package.  Statistical  effect measures  were  logarithmically  transformed,  and  the inverse  variance  method  was  applied.  The  pooled  HPV prevalence  in  endometriosis  was  estimated  using  a random-effects  Poisson-log-normal  model. Heterogeneity  among  studies  was  assessed  using Cochrane’s  Q  test  in  conjunction  with  the  I2  statistic.  A fixed-effects model was selected if P > 0.1 and I2   50%,  significant  heterogeneity  was deemed  present,  and  its  sources  were  explored.  Due  to the  limited  number  of  studies  included,  subgroup analysis  and  publication  bias  assessments  were  not conducted. The significance level was set at α = 0.05.  Quality assessment and risk of bias In  the  current  study,  the  quality  of  the  included literature  was  rigorously  assessed,  and  the  items outlined  in  the  PRISMA  statement  were  strictly followed.  Due  to  the  inclusion  of  fewer  than  10 studies[13-19],  publication  bias  could  not  be  evaluated using Egger’s test, which limited the statistical power of the analysis. The quality assessment of the included studies  was  independently  conducted  by  two investigators,  with  cross-verification.  In  cases  of disagreement,  a  third  investigator  was  consulted  to resolve the discrepancies. For  cross-sectional  studies[16-19],  the  quality  of  the research  was  assessed  using  the  quality  assessment scale  recommended  by  the  Agency  for  Healthcare Research  and  Quality  (AHRQ).  This  scale  comprises 11 items, each of which is answered with "yes," "no," or  "unclear."  The  scores  range  from  zero  to  11,  with 8–11  stars  indicating  high  quality,  4–7  indicating moderate quality, and 0–3 indicating low quality. For  case-control  studies[13-15],  the  quality  of  the study was assessed using the Newcastle-Ottawa Scale (NOS),  which  evaluates  three  domains:  the  selection of  cases  and  controls,  the  comparability  between them,  and  the  assessment  of  exposure.  Scores  range from zero to 9, with 7–9 stars indicating high quality, 4–6  indicating  moderate  quality,  and  0–3  indicating low quality.  Case-control study  Study subjects and grouping A  case-control  study  was  conducted  to  analyze  the clinical  data  of  patients  who  underwent  surgical treatment for endometriosis at Nanjing Maternity and Child  Health  Care  Hospital  (also  known  as  the Women’s  Hospital  of  Nanjing  Medical  University) between January 2017 and June 2022. Based on their HPV  infection  status,  patients  were  categorized  into two groups: the HPV(−) group and the HPV(+) group, which  included  both  high-risk  and  low-risk  HPV(+) subgroups.  Ethics approval and consent to participate The  current  study  received  approval  from  the HPV infection and endometriosis 3 Unproofed Clinical  Research  Ethics  Committee  of  Nanjing Maternity  and  Child  Health  Care  Hospital  (Approval No.  2022KY-100)  and  was  conducted  in  accordance with the Declaration of Helsinki. The study adhered to established ethical standards.  Inclusion and exclusion criteria The  inclusion  criteria  included:  (1)  Women  of reproductive  age  ≤  40  years  at  the  time  of  surgery; and  (2)  Diagnosis  of  endometriosis  confirmed  by postoperative  pathological  results.  The  exclusion criteria included: (1) Coexisting diseases significantly impairing fertility (e.g., adenomyosis, uterine fibroids, etc.);  (2)  Concurrent  malignancies  (e.g.,  endometrial cancer, cervical cancer, ovarian cancer, etc.); (3) Loss to follow-up post-surgery due to personal reasons; and (4) Missing clinical data.  Research methods HPV infection was detected by HPV DNA testing, the WHO-recommended primary test. The patient was positioned  in  the  lithotomy  position.  The  cervix  was exposed  using  a  speculum,  and  cervical  secretions were  collected  using  an  HPV  sampling  brush.  HPV nucleic  acid  detection  and  genotyping  kit  (PCR capillary  electrophoresis  fragment  analysis)  (Health Genetech  Co.,  Ltd.,  Guangzhou,  China)  was  used  to detect  HPV  DNA  in  patients'  cervical  secretions, including high-risk HPV types 16, 18, 26, 31, 33, 35, 39,  45,  51,  52,  53,  56,  58,  59,  66,  68,  73,  and  82,  as well as low-risk HPV types 6, 11, 42, 43, 44, 81, and 83  according  to  the  manufacturer's  instructions.  If  a patient  was  infected  with  at  least  one  high-risk  HPV type,  she  was  considered  to  be  positive  for  high-risk HPV. The  intraoperative  scoring  and  staging  of endometriosis  were  performed  based  on  the  revised American  Fertility  Society  (rAFS)  classification, wherein  points  were  allocated  as  follows:  for endometriotic lesions, superficial peritoneal implants  3 cm received 1, 2, and 4 points, respectively,  while  deep  peritoneal  implants  of corresponding  sizes  received  2,  4,  and  6  points; superficial  ovarian  implants    3 cm  scored  1,  2,  and  4  points  per  side,  and  deep ovarian  implants  received  4,  16,  and  20  points; posterior  cul-de-sac  obliteration  contributed  4  points for  partial  and  40  points  for  complete  closure; adhesions  were  scored  based  on  density  and  extent, with thin adhesions scoring 1, 2, or 4 points and dense adhesions scoring 4, 8, or 16 points for    2/3  enclosure  of  each  adnexal  structure  (ovaries and  fallopian  tubes),  and  complete  enclosure  of  the fimbriated  end  automatically  scored  16  points;  the total score was categorized into stage I (1–5), stage II (6–15), stage III (16–40), or stage IV (> 40)[20]. The  endometriosis  fertility  index  (EFI)  was calculated  according  to  the  criteria  summarized  and refined  by  Adamson  et al[21],  which  comprises  two components: the total history factor score and the total surgical  factor  score.  The  total  surgical  factor  score includes  both  the  lowest  functioning  (LF)  score  and the r-AFS score. The left and right fallopian tubes and ovaries  are  scored  individually,  and  the  LF  score  is determined  by  summing  the  lowest  scores  from  each side. If one ovary is absent, the LF score is calculated as twice the lowest score of the contralateral side. Preoperative  cancer  antigen  125  (CA125) concentrations  were  measured  using  the chemiluminescent  reagent  kit  (Cat  #  07026986190, Roche,  Basel,  Switzerland)  by  a  COBAS  6 000 analyzer  (Roche).  Briefly,  after  a  first  12  µL-sample incubation  with  biotinylated  and  ruthenium-labeled CA125  antibodies  to  form  the  sandwich  complex, streptavidin-coated  microparticles  were  added  in  a second  step  to  bind  the  complex  via  biotin- streptavidin.  The  microparticles  were  then magnetically  immobilized  on  the  electrode  surface. After  washing,  the  voltage-stimulated chemiluminescence  was  measured.  Results  were calculated  from  an  instrument-specific  two-point calibration curve and the cobas-link master curve.  Statistical methods Data  processing  and  statistical  analysis  were conducted  using  SPSS  software  version  26.0. Quantitative  data  that  were  not  normally  distributed were  presented  as  medians  with  25th  and  75th percentiles,  and  intergroup  comparisons  were performed  using  the  non-parametric  test  (Mann- Whitney  U  test).  Qualitative  data  were  expressed  as frequencies  and  percentages  (%),  and  group comparisons were analyzed using the Chi-square test. For 2 × 2 contingency tables, Pearson's Chi-square test was used when the minimum expected count was  ≥ 5 and  the  sample  size  (n)  exceeded  40;  otherwise, Fisher’s  exact  test  was  used.  A  two-sided  test  with  a P-value < 0.05 was considered statistically significant.

Meta-analysis of the association between HPV infection and endometriosis and infertility To  investigate  the  association  between  HPV infection  and  endometriosis  risk  and  infertility,  we initially  searched  for  published  articles  on  HPV 4 Li W et al. J Biomed Res, 2025, 39(0) Unproofed infection,  endometriosis,  and  fertility  outcomes  in patients  with  endometriosis,  yielding  a  total  of  283 articles. After removing 80 duplicates, 51 studies were screened  based  on  their  paper  titles,  abstracts,  and reliability, and 46 were identified as potentially eligible for  inclusion  and  were  retrieved  in  full  text.  Among these,  39  studies  were  excluded  for  not  meeting  the inclusion  criteria,  including  one  without  a  control group[22] and another with an irrelevant target disease[8]. Seven  studies  met  the  qualitative  and  quantitative criteria  for  our  meta-analysis[13-19]  (Fig. 1).  However, only  two  articles  explored  the  association  between HPV  infection  and  infertility  in  patients  with endometriosis.  We  first  conducted  a  meta-analysis  to assess  the  association  between  HPV  infection  and endometriosis  risk,  between  high-risk  HPV  infection and endometriosis risk, and between HPV infection and infertility  in  patients  with  endometriosis.  The  main characteristics  of  the  included  studies  are  described  in Table 1.    Records identified from database searching: PubMed, EMBASE, Web of Science (n=283) Additional records identified through other sources, manual search (n=0) Total records before removal of duplicates (n=283) Duplicate records removed (n=80) Records screened via title and abstract (n=203) Records excluded due to irrelevance (n=157) Full-text articles chosen as potentially eligible (n=46) Studies included in meta-analysis (n=7) Record excluded with reason: (n=39) Non-English (n=1) Conference abstract (n=2) Review (n=34) No control (n=1) Non-target disease (n=1) IdentificationScreeningIncluded   Fig. 1     Flow diagram of studies identified, included, and excluded.   Table 1 Characteristics of included studies Study Hong et al (2023)[17] Moslehi et al (2023)[18] Oppelt et al (2010)[13] Heidarpour et al (2017)[16] Rocha et al (2019)[15] Okyay et al (2023)[19] Vestergaard et al (2010)[14] Country United States Iran Germany Iran Brazil Turkey Denmark Design Cross-sectional Cross-sectional Case-control Cross-sectional Case-control Cross-sectional Case-control With endometriosis 129 81 56 50 29 410 32 　HPV(+) 57 20 14 13 24 202 1 　HPV(−) 72 61 15 37 5 208 31 　Not available 0 0 27 0 0 0 0 Without endometriosis 1 639 – 13 49 31 – 20 　HPV(+) 765 – 9 5 11 – 2 　HPV(−) 874 – 0 44 20 – 18 　Not available 0 – 4 0 0 – 0 High-risk HPV types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82 16, 18, 35, 51, 52, 53, 68 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 68 Low-risk HPV types 6, 11, 40, 42, 54, 55, 61, 62, 64, 67, 69, 70, 71, 72, 81, 83, 84, 89, IS39 3,6,11,40 6, 11, 42, 43, 44 – 6, 11, 30, 34, 40, 42, 43, 44, 54, 55, 61, 62, 64, 67, 69, 70, 72, 74, 81, 83, 84, 91 – 35, 70, 90 HPV detection

Linear Array HPV Genotyping Test HPV Direct Flow CHIP PCR-based ELISA HPV High-risk Typing PCR Kit Single-target PCR Cobas 4800 HPV Test PCR using the degenerate FAP primer pair Diagnosis

Questionnaire Clinical symptoms, surgery, or imaging Surgery Surgery Surgery Surgery or imaging Surgery Quality Moderate Moderate Moderate Moderate Moderate Moderate Moderate Abbreviation: HPV, human papillomavirus. HPV infection and endometriosis 5 Unproofed No significant difference was observed in HPV infection rates between endometriosis patients and controls Current evidence on overall rates of HPV infection in individuals with endometriosis remains limited. Our systematic  review  identified  only  two  comparative studies  evaluating  the  overall  HPV  infection  rates  in control  and  endometriosis  patients  and  four  studies specifically  evaluating  the  high-risk  HPV  infection rates  in  control  and  endometriosis  patients.  Using random-effects  meta-analysis  models,  we  found  no statistically  significant  difference  in  either  overall HPV  infection  rates  (OR:  2.60,  95%  CI:  0.28–23.87) or  high-risk  HPV  infection  rates  (OR:  1.68,  95%  CI: 0.49–5.75) with respect to endometriosis risk (Fig. 2). These  non-significant  associations  indicate  that current  evidence  does  not  sufficiently  support  an epidemiological  association  between  HPV  infection and endometriosis risk.    A EMS(+) EMS(−) EMS(+) EMS(−) Study or Subgroup Events Total Events Total Weight OR (95% CI) OR (95% CI) Rodrigo et al 2018 24 29 11 31 46.6% 8.73 (2.60, 29.33) Yun et al 2023 57 129 765 1 639 53.4% 0.90 (0.63, 1.30) Total (95% CI) 158 1 670 100% 2.60 (0.28, 23.87) Total events 81 776 Heterogeneity: Tau2=2.361 2; Chi2=12.34, df=1 (P=0.000 4); I2=91.9% Test for overall effect: Z=0.85 (P=0.397 8) B Study or Subgroup Events Total Events Total Weight OR (95% CI) OR (95% CI) Anna L.et al 2010 1 32 2 20 14.3% 0.29 (0.02, 3.43) Mitra et al2016 13 50 5 49 26.5% 3.09 (1.01, 9.48) Rodrigo et al2018 19 29 7 31 26.4% 6.51(2.09, 20.33) Yun et al2023 31 129 489 1 639 32.8% 0.74(0.49, 1.13) Total (95% CI) 240 1 739 100.0% 1.68(0.49, 5.75) Total events 64 503 Heterogeneity: Tau2=1.157 3; Chi2=17.11, df=3 (P=0.000 7); I2=82.5% Test for overall effect: Z=0.83(P=0.408 1) 0.1 0.5 1 2 10 Favors HPV (+) Favors HPV (−) Favors HPV (−) 0.1 0.5 1 2 10 Favors HPV (+)   Fig. 2   The association of HPV infection (A) and high-risk HPV infection (B) with endometriosis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using inverse-variance weighting. The area of each square corresponds to the study-specific weight in the meta-analysis. Horizontal lines span the 95% CI range. Solid vertical ticks indicate point estimates. The red squares denote studies with smaller samples (n  < 100), whose wider confidence intervals indicate lower precision. The diamond reflects the pooled estimate with heterogeneity. Studies are labeled by the first author and publication year. Abbreviations: EMS, endometriosis.   Regarding  absolute  prevalence,  our  analysis incorporated  three  studies  comprising  239 endometriosis  patients,  among  whom  101  cases (42.3%)  were  HPV(+),  and  six  studies  comprising 679  endometriosis  patients,  among  whom  280  cases (41.2%)  were  infected  with  high-risk  HPV.  The random-effects  model  estimated  a  pooled  HPV infection  prevalence  of  46%  (95%  CI:  0.23–0.90) and  a  pooled  high-risk  HPV  infection  prevalence  of 36%  (95%  CI:  0.23–0.56)  in  endometriosis  patients (Fig. 3).  Conflicting evidence on HPV infection and endometriosis-associated infertility Current  research  presents  contradictory  findings regarding  the  association  between  HPV  infection  and infertility  in  endometriosis  patients[18-19].  Our  analysis identified  two  studies  with  opposing  conclusions.  A random-effects  meta-analysis  revealed  no  statistically significant  difference  in  HPV  infection  rates  between the infertility group of patients with endometriosis and those  with  normal  pregnancies  (OR:  0.73,  95%  CI: 0.07–7.20)  (Fig. 4).  Considering  the  small  sample 6 Li W et al. J Biomed Res, 2025, 39(0) Unproofed sizes  in  both  studies,  further  investigation  into  the association  between  HPV  infection  and  infertility  in patients with endometriosis is warranted.  The case-control analysis revealed that HPV infection was significantly associated with reduced live birth rate among endometriosis patients under 40 years of age.  The postoperative live birth rate was significantly lower in the HPV(+) group compared with the HPV(−) group To  further  investigate  the  effects  of  HPV  infection on  the  fertility  of  women  with  endometriosis,  we conducted a case-control study. A total of 432 patients with  endometriosis  were  included  in  the  study,  of whom  66  were  infected  with  HPV  before  surgery. This group comprised 49 patients with high-risk HPV infections  (including  10  patients  with  HPV  types  16 and  18,  four  of  whom  had  mixed  infections),  13 patients  with  low-risk  HPV  infections,  and  four patients  with  both  high-risk  and  low-risk  HPV infections.  The  remaining  366  patients  were  in  the HPV(−) group. Baseline characteristics, including age,   Study or Subgroup Events Total Weight Proportion (95%CI) Zohreh et al 2023 20 81 31.6% 0.25 (0.16, 0.36) Rodrigo et al 2018 24 29 34.3% 0.83 (0.64, 0.94) Yun et al 2023 57 129 34.1% 0.44 (0.35, 0.53) Total (95% CI) 239 100% 0.46 (0.23, 0.90) Total events 101 Heterogeneity: Tau2=0.340 4; Chi2=44.51, df=2 (P<0.000 1); I2=95.5% Study or Subgroup Events Total Weight Proportion(95%CI) Peter et al 2010 14 29 18.4% 0.48(0.29, 0.67) Rodrigo et al 2018 19 29 19.8% 0.66(0.46, 0.82) Mitra et al 2016 13 50 17.2% 0.26(0.15, 0.40) Emre et al 2023 202 410 21.1% 0.49(0.44, 0.54) Anna L.et al 2010 1 32 4.2% 0.03 (0.00, 0.16) Yun et al 2023 31 129 19.3% 0.24 (0.17, 0.32) Total (95% CI) 679 100% 0.36(0.23, 0.56) Total events 280 Heterogeneity: Tau2=0.235 5; Chi2=39.07, df=5 (P<0.000 1); I2=87.2% 0.2 0.4 0.6 0.8 0.2 0.4 0.8 1.0 A B   Fig. 3   Forest plot analysis comparing prevalence rates of any HPV infection (A) versus high-risk HPV subtypes (B) among women with endometriosis.  Proportions  with  95%  confidence  intervals  (CIs)  were  calculated  using  a  random-effects  Poisson-log-normal  model. The area of each square corresponds to the study-specific weight in the meta-analysis. Horizontal lines span the 95% CI range. Solid vertical ticks  indicate  point  estimates.  The  red  squares  denote  studies  with  smaller  samples  (n  <  100),  whose  wider  confidence  intervals  indicate lower precision. The diamond reflects the pooled estimate with heterogeneity. Studies are labeled by the first author and publication year.   Infertility (+) Infertility (−) Study or Subgroup Events Total Events Total Weight OR (95% CI) OR (95% CI) Zohreh et al 2023 3 31 17 50 46.8% 0.21 [0.06, 0.78] Emre et al 2023 31 47 171 363 53.2% 2.18 [1.15, 4.12] Total (95% CI) 100% 0.73 [0.07, 7.20] Total events 34 188 Heterogeneity: Tau2=2.473 4; Chi2=9.77, df=1 (P=0.001 8); I2=89.8% Test for overall effect: Z=−0.27 (P=0.783 7) 0.1 0.5 1 2 10 Favors HPV (+) Favors HPV (−)   Fig. 4   HPV infection and infertility risk in endometriosis: a random-effects meta-analysis of two cross-sectional studies. Odds ratios (ORs)  with  95%  confidence  intervals  (CIs)  were  calculated  using  inverse-variance  weighting.  The  area  of  each  square  corresponds  to  the study-specific  weight  in  the  meta-analysis.  Horizontal  lines  span  the  95%  CI  range.  Solid  vertical  ticks  indicate  point  estimates.  The  red squares denote studies with smaller samples (n  < 100), whose wider confidence intervals indicate lower precision. The diamond reflects the pooled estimate with heterogeneity. Studies are labeled by the first author and publication year. IV: inverse variance. HPV infection and endometriosis 7 Unproofed endometriosis score, EFI, CA125 levels, unilateral and bilateral  disease,  and  endometriosis  stage,  were compared  between  the  two  groups.  No  statistically significant  differences  were  found  (P  >  0.05  for  all) (Table 2). However,  the  postoperative  pregnancy  rate  was lower  in  the  HPV(+)  group  compared  with  the HPV(−)  group  (15.2%  vs.  24.3%),  and  the  infertility clinic visit rate was higher in the HPV(+) group than in  the  HPV(−)  group  (18.2%  vs.  14.2%)  ,  although these  differences  did  not  reach  statistical  significance (P  =  0.103  and  P  =  0.403,  respectively).  In  contrast, the  postoperative  live  birth  rate  was  significantly lower in the HPV(+) group than in the HPV(−) group (10.6% vs. 21.0%; P = 0.049) (Table 2).  No significant differences were observed in postoperative live birth rates between endometriosis patients with low-risk and high-risk HPV infections Subgroup  analysis  of  endometriosis  patients  with low-risk  (13  patients)  and  high-risk  HPV  infections (53 patients) revealed that the postoperative live birth rate  was  higher  in  the  low-risk  group  (15.4%  vs. 9.4%).  However,  this  difference  was  not  statistically significant (P > 0.05) (Table 3).  Among endometriosis patients achieving postoperative pregnancy, those with high-risk HPV coinfection demonstrated a 24.3% reduction in live birth rates compared with HPV(−) or low-risk HPV- infected counterparts A  further  analysis  of  pregnancy  outcomes  in endometriosis  patients  with  successful  postoperative pregnancies revealed that the live birth rate was lower in those with high-risk HPV infection compared with patients  with  no  HPV  infection  or  low-risk  HPV infection (62.5% vs. 86.8%). However, the difference was not statistically significant (P = 0.099) (Table 4).

It  has  been  suggested  that  HPV  infection  may influence  the  development  of  endometriosis[8].  HPV infection  has  been  detected  in  both  the  upper  and lower genital tracts of infertile patients and those with endometriosis[15].  Notably,  two  studies  that  detected HPV  infection  within  endometriosis  lesions  indicated that HPV might ascend through the genital tract to the uterine  cavity,  potentially  contributing  to  the development  of  endometriosis[13-14].  However,  the   Table 2 Association of HPV coinfection with clinicopathological features and fertility outcomes in endometriosis patients Variable HPV(+) group (n=66) HPV(−) group (n=366) P value Age [years, median (Q1, Q3)] 32 (30.0, 36.0) 31 (28.0, 36.0) 0.360a Endometriosis scoring [points, median (Q1, Q3)] 40 (32.0, 73.0) 40 (28.0, 73.0) 0.526a EFI [points, median (Q1, Q3)] 8.0 (7.0, 9.0) 8 .0(7.0, 9.0) 0.569a CA125 [U/ml, median (Q1, Q3)] 50.68 (32.8, 77.6) 46.72 (29.9, 77.2) 0.795a Affected area [n (%)] 　One 44 (66.7%) 241 (65.8%) 0.897b 　Both 22 (33.3%) 125 (34.2%) Endometriosis staging [n (%)] 　Stage 3 36 (54.5%) 181 (49.5%) 0.446b 　Stage 4 30 (45.5%) 185 (50.5%) Infertility clinic visit [n (%)] 　Yes 12 (18.2%) 52 (14.2%) 0.403b 　No 54 (81.8%) 314 (85.8%) Postoperative pregnancy [n (%)] 　Yes 10 (15.2%) 89 (24.3%) 0.103b 　No 56 (84.8%) 277 (75.7%) Postoperative birth [n (%)] 　Yes 7 (10.6%) 77 (21.0%) 0.049b 　No 59 (89.4%) 289 (79.0%) Data 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 125; EFI, endometriosis fertility index; HPV, human papillomavirus. 8 Li W et al. J Biomed Res, 2025, 39(0) Unproofed

of  our  meta-analysis  revealed  no  significant association  between  HPV  infection  (including  high- risk HPV) and endometriosis risk. Further analysis of the prevalence of HPV infection among patients with endometriosis,  based  on  seven  studies,  indicated  that the  overall  prevalence  of  HPV  infection  in  patients with  endometriosis  was  46%,  with  a  36%  prevalence of high-risk HPV infection. While the reported overall HPV  infection  rate  in  women  ranges  from  11.5%  to 13.1%,  with  high-risk  HPV  infection  rates  varying between  9.67%  and  24.1%[23-27],  these  data  suggest that  HPV  infection  may  be  more  prevalent  among patients  with  endometriosis,  which  is  consistent  with the  findings  of  Heidarpour  et al[16].  Nevertheless, significant  heterogeneity  among  studies  and  the limited  number  of  included  investigations  may introduce  potential  bias  and  reduce  statistical  power, highlighting the need for large-scale research to better elucidate  both  the  prevalence  of  HPV  infection  in endometriosis patients and its potential etiological role in disease development. In  patients  with  ovarian-type  endometriosis,  large ovarian  chocolate  cysts  can  compress  the  ovarian cortex, leading to atrophy and reduced ovarian reserve function[28]. The current standard surgical approach for endometriosis  involves  removing  as  much  of  the   Table 3 Differential effects of high-risk HPV and low-risk HPV infection on clinicopathology and fertility in women with endometriosis and concurrent HPV infection Variable Low-risk HPV group (n=13) High-risk HPV group (n=53) P value Age [years, median (Q1, Q3)] 33 (30.5, 36.5) 32 (29.5, 36.0) 0.571a Endometriosis Scoring [points, median (Q1, Q3)] 36 (28.0, 84.0) 40 (32.0, 70.0) 0.577a EFI [points, median (Q1, Q3)] 8.0 (6.5, 8.0) 8.0 (7.0, 9.0) 0.173a CA125 [U/ml, median (Q1, Q3)] 36.04 (20.8, 70.8) 50.77 (34.1, 82.0 ) 0.249a Affected area [n (%)] 　One 10 (76.9%) 34 (64.2%) 0.518c 　Both 3 (23.1%) 19 (35.8%) Endometriosis staging [n (%)] 　Stage 3 8 (61.5%) 28 (52.8%) 0.572b 　Stage 4 5 (38.5%) 25 (47.2%) Infertility clinic visit [n (%)] 　Yes 3 (23.1%) 9 (17.0%) 0.691c 　No 10 (76.9%) 44 (83.0%) Postoperative pregnancy [n (%)] 　Yes 2 (15.4%) 8 (15.1%) 1.000c 　No 11 (84.6%) 45 (84.9%) Postoperative live birth [n (%)] 　Yes 2 (15.4%) 5 (9.4%) 0.617c 　No 11 (84.6%) 48 (90.6%) Data 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 125; EFI, endometriosis fertility index; HPV, human papillomavirus.   Table 4 Effect of high-risk HPV infection on post-surgical live birth outcomes in endometriosis patients achieving pregnancy Variable HPV(−) and low-risk HPV infection group (n=91) High-risk HPV infection group (n=8) P value Postoperative live birth [n (%)] 　Yes 79 (86.8%) 5 (62.5%) 0.099 　No 12 (13.2%) 3 (37.5%) Data are presented as n (%). Fisher’s exact test was used. Abbreviation: HPV, human papillomavirus. HPV infection and endometriosis 9 Unproofed ectopic  tissue  as  possible,  but  this  may  result  in adverse outcomes, such as impaired ovarian function, pelvic  adhesions,  and  laparoscopic  surgical complications,  all  of  which  can  affect  postoperative pregnancy  outcomes.  Endometriosis  can  result  in  the accumulation  of  various  toxic  cytokines  (e.g., inflammatory  cytokines  and  active  macrophages)  in the peritoneal fluid and uterus, which induce a chronic inflammatory  response  in  the  pelvic  cavity[29].  This chronic  inflammation  can  contribute  to  infertility  and miscarriage. Additionally, HPV infection may further trigger an immune response or increase the production of  proinflammatory  cytokines[30-32],  potentially contributing to infertility and pregnancy loss. Nonetheless,  limited  research  exists  on  the  impact of  HPV  infection  on  pregnancy  rates  and  fertility  in patients  with  endometriosis.  The  only  two  studies  on the  association  between  HPV  infection  and  infertility in  endometriosis  have  reached  conflicting conclusions[18-19].  Key  factors  contributing  to  these differences  include  sample  size  (410  vs.  81),  HPV sampling  location  (cervical  scrapings  vs.  both  the exocervix  and  tissue  samples),  HPV  testing  methods (Cobas 4 800 HPV Test vs. HPV Direct Flow CHIP), and confounding variables such as patient age (30–65 years vs. 20–50 years), country (Turkey vs. Iran), and the  types  of  HPV  infections  in  the  study  populations (14  high-risk  HPVs  vs.  six  high-risk  HPVs  and  five low-risk  HPVs,  with  HPV  types  6  and  11  being  the most  prevalent  in  endometriosis  patients).  For example, Okyay et al[19] included only high-risk HPV types  in  their  study  and  concluded  that  the  infertility rate was significantly higher in the HPV16/18-infected group.  In  contrast,  Moslehi  et al[18]  included  11  HPV types in their study (six of which were high-risk HPV infections),  with  fewer  than  60%  of  infections involved  high-risk  HPV  types,  yet  the  infertility  rate in  the  HPV-infected  group  was  significantly  lower than  that  in  the  control  group.  Considering  these discrepancies,  we  further  analyzed  the  association between HPV infection and infertility in patients with endometriosis in our sample. Because  several  studies  included  in  our  meta- analysis  classified  high-risk  HPV  according  to  the IARC  classification  (14  definitive  carcinogenic  types in  group  1  and  four  possibly  carcinogenic  types  in group  2B),  our  case-control  study  adopted  the  same criteria. Using this definition, we found the following prevalence  rates:  high-risk  HPV  in  49/66  (74.2%), low-risk  HPV  in  13/66  (19.7%),  and  high-risk/low- risk  co-infections  in  4/66  (6.1%).  The  postoperative live  birth  rate  was  significantly  lower  in  the  HPV(+) group  than  in  the  HPV(-)  group.  Stratified  analysis further  showed  a  higher  postoperative  liver  birth  rate in  the  low-risk  HPV  infection  group  compared  with the  high-risk  HPV  infection.  These  findings significantly differ from those reported by Moslehi et al,  but  are  more  closely  aligned  with  the  research conducted by Okyay et al[18-19], supporting a potential association  between  high-risk  HPV  infection  and worse  fertility  outcomes  in  patients  with endometriosis.  This  observation  is  also  in  line  with our  subgroup  analysis,  which  indicated  a  lower postoperative  live  birth  rate  in  the  high-risk  HPV group  compared  with  the  low-risk  HPV  infection group  (9.4%  vs.  15.4%).  Nevertheless,  the  limited sample size in our study reduced the statistical power of  our  findings.  Further  investigations  are  warranted to  elucidate  the  distinct  effects  of  low-risk  versus high-risk  HPV  infections  on  the  infertility  of endometriosis patients. High-risk  HPV  infection  appears  to  exert  a measurable  influence  on  reproductive  outcomes. However,  current  studies,  including  our  own,  are limited  by  relatively  small  sample  sizes  and  low statistical  power.  Furthermore,  the  results  may  have been  influenced  by  various  confounding  factors, including  the  HPV  detection  methods,  definitions  of high-risk HPV, regional variations in HPV genotypes, socioeconomic  status  (particularly  quality  of  life  and marital status), timing of viral exposure, patients’ age, and  the  ongoing  fertility  intentions  of  both  patients and  their  family  members.  These  variables  likely impact  both  pregnancy  rates  and  overall  fertility outcomes,  thereby  introducing  additional  complexity to the interpretation of our findings. While  our  meta-analysis  demonstrated  no etiological  association  between  HPV  infection  and endometriosis  development,  the  case-control  study revealed significantly reduced postoperative live birth rates  among  HPV-positive  endometriosis  patients compared  with  their  HPV-negative  counterparts. Furthermore,  the  subgroup  analysis  showed  that  the postoperative live-birth rate was higher in the low-risk HPV  group  than  in  the  high-risk  HPV  group.  These findings  indicate  that  systematically  evaluating  and managing  concurrent  HPV  infection  in  patients  with endometriosis  may  protect  fertility  and  improve reproductive  outcomes,  offering  new  intervention directions  for  patients  with  both  endometriosis  and HPV infection-related infertility. However, the limited sample size in our study reduced the statistical power of  these  findings.  Therefore,  future  prospective  and longitudinal  studies  with  larger  sample  sizes  and comprehensive HPV-genotype analyses are warranted to validate these findings.  10 Li W et al. J Biomed Res, 2025, 39(0) Unproofed Funding This  work  was  supported  by  the  National  Natural Science Foundation of China (Grant Nos. 82472707 to X.J.  and  81901456  to  W.L.),  Jiangsu  Province Capability  Improvement  Project  through  Science, Technology,  and  Education,  Jiangsu  Provincial Medical  Key  Discipline  (Grant  No.  ZDXK202211  to X.J.),  and  Jiangsu  Province  Graduate  Practical Innovation  Program  (Grant  No.  SJCX24_0759  to Z.W.).  Acknowledgment None.  Data availability statement The  datasets  generated  or  analyzed  during  the current  study  are  not  publicly  available  as  they  form part  of  an  ongoing  investigation,  but  are  available from  the  corresponding  author  upon  reasonable request.

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