{"paper_id":"c02e4969-a27d-4414-91ec-da5ec8701b1a","body_text":"REVIEWS © Copyright by Wydawnictwo Continuo\nAssociation of endometriosis with human papillomavirus \n(HPV) infection: a systematic review\nAnnA  Sienko 1, A, E, F , iSAbellA  Weber 1, A, E, F , Alek SAndrA  Urb An 2, A, D, E,   \nORCID ID: 0009-0008-0350-2088           ORCID ID: 0009-0007-6729-7469                     ORCID ID: 0009-0007-6729-7469, \nCArolyn Sz Wed 3, E, JACek Sienko 2, A, D, E \nORCID ID: 0009-0001-9172-8931            ORCID ID: 0000-0002-6277-5237\n1 University of Cambridge, Clinical School of Medicine, Cambridge, United kingdom\n2 2nd department of obstetrics and Gynaecology, Medical University of Warsaw, Poland\n3 department of Social Medicine and Public Health, Medical University of Warsaw, Warsaw, Poland\nA – Study design, B – Data Collection, C – Statistical Analysis, D – Data Interpretation, E – Manuscript Preparation, F – literature \nSearch, G – Funds Collection\nEndometriosis is defined as the presence of endometrial tissue outside of the uterine cavity. It is a chronic disease affecting \napproximately 10% of women. In addition to producing a vast array of symptoms, including chronic pelvic pain and dysmenorrhea, the \ncondition significantly impacts quality of life. Over the past century, several theories have attempted to explain the pathogenesis of \nthis complex disease. Recent studies have investigated the potential role of human papillomavirus (HPV) infection in the development \nof endometriotic lesions. The objective of this review was to conduct a search of online databases (Embase, Medline and PubMed) \nfor available literature from June 2013 to June 2023 concerning the association between HPV and endometriosis. After screening 110 \narticles, 23 studies met the eligibility criteria, and 8 were included in the systematic review. Out of the 8 reviewed papers, 3 described \na statistically significant correlation between HPV infection and endometriosis. 3 others only demonstrated a higher incidence of HPV \ninfection in patients with confirmed endometriosis. A difference in the dominant type of HPV serotype among patients diagnosed with \nendometriosis was also observed. Given these results, it is difficult to propose a viral origin of the disease. Further research is necessary \nto determine the role of HPV infection in the development of endometriosis. \nKey words: endometriosis; papillomavirus infections, viral sexually transmitted diseases.\nSummary\nISSN 1734-3402, eISSN 2449-8580\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International \n(CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/).\nSienko A, Weber I, Urban A, Szwed C, Sienko J. Association of endometriosis with human papillomavirus (HPV) infection: a systematic \nreview. Fam Med Prim Care Rev 2023; 25(4): 459–465, doi: https://doi.org/10.5114/fmpcr.2023.131834.\nFamily Medicine & Primary Care Review 2023; 25(4): 459–465, https://doi.org/10.5114/fmpcr.2023.131834\nBackground\nEndometriosis is a chronic inflammatory disease that affects \n5–10% of women of reproductive age worldwide [1]. It is a de-\nbilitating condition characterised by symptoms such as chronic \npelvic pain, dysmenorrhea, dyspareunia, dysuria and infertility \n[2]. Traditionally, endometriosis has been defined as the surgical \ndetection of endometriotic tissue outside of the uterine cavity \n[3]. However, there has been a recent shift towards a more pa-\ntient-focused definition that considers its complex, chronic and \nsystemic nature. This updated understanding takes into account \nthe involvement of various tissues, as well as the cellular and \nmolecular origins of the disease [4]. \nEndometriosis not only has significant physical effects but \nalso profound psychological consequences and an economic im-\npact. It significantly compromises the quality of life of affected \npatients and increases the risk of developing depression and \nanxiety disorders [5, 6]. In 2002, the economic burden of en-\ndometriosis in the United States alone reached $22 billion [7]. \nNumerous theories have emerged in an attempt to unravel \nthe pathogenesis of endometriosis. The widely embraced retro-\ngrade menstruation theory, proposed by Sampson, suggests the \ninfiltration of endometrial tissue into the pelvic cavity during \nmenstruation [3]. However, the occurrence of endometriosis \nin individuals without a uterus challenges the exclusive validity \nof this theory, pointing towards the involvement of alternative \nmechanisms [8]. Another hypothesis, known as coelomic meta-\nplasia, postulates the transformation of mesothelial cells in the \nperitoneum, pleura and ovaries into endometrial-like tissue [9]. \ndespite these theories, the full complexity of endometriosis \nremains enigmatic, as neither these nor other proposed expla -\nnations such as angiogenic spread, lymphogenic spread, stem \ncells or Mullerian rests have provided comprehensive insights. \nFactors including genetic predisposition, epigenetic alterations, \nendocrine influences and aberrant immune responses are be-\nlieved to contribute to the multifaceted development of endo -\nmetriosis [10, 11]. \nInflammation plays a crucial role in endometriosis, although \nit is not yet clear whether it initiates the disease or perpetu-\nates it [1]. A concept of the possible role of infectious agents \nin initiating endometriosis has emerged [12, 13]. The “theory \nof contamination” or “infectious theory” suggests that microor-\nganisms, along with endometrial tissue, can travel to the upper \ngenital tract and peritoneal cavity during retrograde menstrua-\ntion [14]. \nRecent research has highlighted the potential involvement \nof human papillomavirus (HPV) in endometriosis. HPV is a prev-\nalent sexually transmitted infection, encompassing a wide spec-\ntrum of diseases, from low-risk types causing anogenital warts \nto high-risk types associated with anogenital and oropharyngeal \ncancers [15]. Interestingly, most patients infected with HPV do \nnot exhibit discernible clinical signs or symptoms [16]. Conse -\nquently, the role of HPV in endometriosis has attracted atten-\ntion in studies conducted over the past decade [17–20]. Building \nupon these considerations, the current study aims to systemati-\ncally review the existing literature concerning this topic.\n\nA. Sienko et al. • Association of endometriosis with HPV infection\nFamily Medicine & Primary Care Review 2023; 25(4)\n460\nMethods\n \nThe Preferred Reporting Items for Systematic Reviews and \nMeta-Analyses (PRISMA) guidelines were followed to conduct \nthis systematic review. Two authors (A.S. and I.W.) conducted \na comprehensive literature search of the online databases em-\nbase, Medline and PubMed, using keywords: (endometrios*) \nOR (adenomyos*) AND (HPV) OR (human papillomavir*) OR \n(human papilloma vir*), as well as Medical Subject Headings \n(MeSH) terms. Our search was limited to English articles pub -\nlished from June 2013 to June 2023. Additionally, we performed \na manual search of the reference lists of the review articles and \nidentified two relevant citations outside of our accepted time \nframe, which we decided to include in our review. EndNote soft-\nware was used to delete duplicate articles. Title and abstract \nscreening were performed before obtaining the full text of eli -\ngible articles. A flow diagram of the systematic review is shown \nin Figure 1 (PRISMA template).\nResults and discussion\nEndometriosis is characterised as a chronic inflammatory \ndisease that disrupts crucial immune processes. This results in \ninflammation and dysregulated immunomodulation, impairing \nthe ability of immune-associated cells such as macrophages, \nneutrophils, dendritic cells, natural killer cells and mast cells to \nidentify and eliminate ectopic endometrial tissue [21]. While \nthere have been efforts to establish a single theory explain -\ning the development of endometriosis, recent acceptance of \nits multifactorial pathogenesis has shifted the focus towards \nidentifying specific factors that may predispose individuals to \ndevelop this disease. \nHPV infection is widespread in the world’s population and is \none of the most common sexually transmitted diseases world -\nwide. Most sexually active adults will have an HPV infection at \nsome point during their lives, although they may remain un -\naware, as it is typically asymptomatic and resolves spontane-\nously [22]. However, in some cases, persistent HPV infection can \nlead to neoplastic transformation, ultimately resulting in cancer \ndevelopment. This transformation is primarily driven by viral E6 \nand E7 oncoproteins, which exert an anti-apoptotic effect and \npromote cell immortalisation in infected cells [23]. \nInterestingly, similar mechanisms are recognised in the tis-\nsues of individuals with endometriosis. Endometriosis lesions \ndemonstrate invasive biological features, including resistance to \napoptosis and proangiogenic effects [24, 25]. Moreover, women \nwith endometriosis have been found to be more susceptible to \ncertain malignancies, such as ovarian cancer and non-Hodgkin’s \nlymphoma [26]. This increased vulnerability may be attributed \nto shared characteristics of malignancy, such as local invasive \ngrowth and distant implantation.\nNotably, the regulation of HPV genes has been demonstrat-\ned to be positively influenced by oestrogen, aligning with endo-\nmetriosis being an oestrogen-dependent disease [27]. This link \nprompted researchers to investigate the potential correlation \nbetween HPV infection and the development of endometriosis, \ngiven the shared pathophysiological mechanisms and the high \nprevalence of both conditions in the population. The main char-\nacteristics of the studies included are summarised in Table 1.\nIn a case-control study conducted in Germany in 2010, Op-\npelt et al. aimed to investigate the hypothesis that viral infection \nof the endometrium, combined with retrograde menstruation \nand impaired immune response, might increase the likelihood \nof developing endometriotic lesions and their persistence in the \nperitoneal cavity or myometrium [20]. For this purpose, a total \nof 66 endometriosis lesions from 56 patients, which included \nperitoneal (n = 49), ovarian (n = 16) and endometrial (n = 1) \nlesions, were analysed. To detect HPV-DNA and other patho -\ngens, polymerase chain reaction (PCR) amplification was per -\nformed, followed by a specific enzyme-linked immunosorbent \nassay (ELISA). The results were compared to 30 control tissues \nincluding endometrium (n = 14), peritoneum (n = 14), ovary \n(n = 1) and vagina (n = 1) from 13 patients with endometrio-\nsis (patient matched) and 13 patients without endometriosis. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nRecords identified from: \nDatabases (PubMed, \nEmbase, Medline;  \nn = 168) \nRecords removed before \nscreening: \nDuplicate records \nremoved (n = 58) \nRecords screened \n(n = 110) \nRecords excluded \n(n = 86) \nReports sought for retrieval \n(n = 24) \nReports not retrieved \n(n = 1) \nReports assessed for  \neligibility (n = 23) Reports excluded: \nNon-English (n = 2) \nConference abstract (n = 6) \nReview (n = 3) \nNo data of interest (n = 6) \nRecords identified from: \nCitation searching (n = 2) \nReports assessed for \neligibility (n = 2) \nReports excluded \n(n = 0) \nStudies included in review \n(n = 8) \nIdentification of studies via databases Identification of studies via other methods \nIdentification \nScreening \n \nIncluded \nReports sought for retrieval \n(n = 2) \nReports not retrieved \n(n = 0) \nFigure 1. Flow diagram showing the search strategy, screening, eligibility and exclusion criteria\n\nA. Sienko et al. • Association of endometriosis with HPV infection\nFamily Medicine & Primary Care Review 2023; 25(4)\n461\nTable 1. Studies investigating the association between HPV and endometriosis included in the current study\nAuthors and \ndate\nType of study \nand country\nSample size and characteristics Methods Results\nOppelt et al. \n2010 [20]\nCase-control \nstudy (Germany)\n70 patients; 66 endometriosis \nlesions from 56 patients (peri-\ntoneal n = 49, ovarian n = 16, \nendometrium n = 1) 30 control \ntissue samples (endometrium \nand peritoneum) from patient-\nmatched (n = 13) and patients \nwithout endometriosis (n = 13)\n• Surgical isolation of endome-\ntriotic lesions; histological \ndiagnosis\n• HPV detection: tissue sample \nHPV-DNA PCR-based ELISA \ndetection; subtype identifi-\ncation using Invader 2.0 HPV \nHigh-Risk Molecular Assay\n• HPV was detected in 7 \n(11.3%) of 62 interpretable \nendometriosis samples from \nindependent patients (71.4% \nhrHPV and 28.6% mrHPV) \nand in 8 (27.5%) of 29 con-\ntrol tissues (75% hrHPV and \n25% mrHPV)\nVestergaard et \nal. 2010 [19]\nCase-control \nstudy (Denmark)\n32 patients; 32 and 27 eutopic \nendometrial and ectopic (ovar-\nian or peritoneal) endometrio-\nsis samples, respectively, from \nthe same group of patients; \n20 endometrial samples from \nnon-endometriosis patients; \ncervical swabs\n• Surgical isolation of endome-\ntriotic lesions; histological \ndiagnosis\n• HPV detection: cervical \nswab; tissue sample HPV PCR \nanalysis and sequencing; \nfurther subtype identifica-\ntion by BLAST \n• HPV was detected in 1  \n(n = 1/32; 3.1%) and 2  \n(n = 2/20; 10%) eutopic \nendometriotic and non-\nendometriotic samples, \nrespectively (p =  0.62)\n• No HPV was detected in  \nectopic endometriotic \nsamples (n = 0/25)\nHeidarpour et \nal. 2017 [17]\nCross-sectional \nstudy (Iran)\n99 patients; 50 and 49 ovarian \nsamples with and without \nendometriosis, respectively\n• Surgical isolation of endome-\ntriotic lesions; histological \ndiagnosis\n• HPV detection: tissue sample \nHPV PCR analysis; subtype \nidentification by HPV High-\nrisk Typing PCR Kit\n• hrHPV was detected in 13 \n(26%) and 5 (10.2%) of the \nsamples with and without \nendometriosis, respectively  \n(p =  0.041, χ\n2 = 3.16)\nRocha et al. \n2019 [18]\nCase-control \nstudy (Brazil)\n60 patients; 29 and 31 endo-\nmetriosis and non-endometrio-\nsis tissue samples, respectively \n(endometrial tissue, pouch \nof Douglas fluid, uterine tube \nlavage and ovarian biopsy \nsamples); cervicovaginal swabs\n• Surgical isolation of endome-\ntriotic lesions; diagnosis \n• HPV detection: cervicovagi-\nnal swab; tissue sample HPV \nPCR analysis; HPV subtype \nidentification by PCR-RFLP\n• HPV was detected in 24 \n(n = 24/29; 82.8%) and 12 \n(n = 12/31; 38.7%) of the \nsamples with and without \nendometriosis, respectively\n• Over 6-fold increased risk of \ninfection in endometriosis \npatients (OR 6.64, 95% CI \n2.00–22.04; p = 0.001)\n• Increased risk of hrHPV \ninfection in LGT and in UGT \nin endometriosis patients \n(respectively, OR 8.5, 95% CI \n2.50–28.70; p = 0.0002 and \nOR 3.6, 95% CI 1.09–12.30; \np = 0.03)\nMatalliotakis \net al. 2021 [28]\nRetrospective, \nepidemiological \nand noncom-\nparative study \n(Greece)\nClinical, surgical, and pathologi-\ncal records from 860 women \n(1990–2020) with endometrio-\nsis undergoing gynaecological \nsurgical treatment; 27 patients \nwith histologically confirmed \ncervical endometriosis\n• N/A • HPV was detected in 16  \n(n = 16/27; 59.2%) samples \nwith cervical endometriosis \n(p < 0.05) \nHong et al. \n2023 [33]\nCross-sectional \nstudy (US)\n129 patients with endometrio-\nsis; cervicovaginal swabs\n• Self-report of physician-\ndiagnosed endometriosis \ncollected via health ques-\ntionnaire\n• HPV detection: cervicovagi-\nnal swab genotyping \n• HPV and hrHPV was diag-\nnosed in 57 (n = 57/129; \n36.9%; p = 0.35) and 31  \n(n = 31/129; 19.8%; p = 0.15) \npatients with endometriosis, \nrespectively \n• No significant association \nwas found between the \nprevalence of hrHPV and the \ndiagnosis of endometriosis \n(aPR 0.71, 95% CI 0.44–1.14)\n• Prevalence of HPV in women \nwith endometriosis was \nhigher in participants with \nhealth insurance than those \nwithout (respectively, aPR \n1.44, 95% CI 0.94–2.20 and \naPR 0.71, 95% CI 0.50–1.03; \np = 0.01)\n\nA. Sienko et al. • Association of endometriosis with HPV infection\nFamily Medicine & Primary Care Review 2023; 25(4)\n462\nTable 1. Studies investigating the association between HPV and endometriosis included in the current study\nAuthors and \ndate\nType of study \nand country\nSample size and characteristics Methods Results\nMoslehi et al. \n2023 [30]\nCross-sectional \nstudy (Iran)\n81 endometriotic tissue \nsamples (endometrial tissue, \npouch of Douglas fluid, utero-\nsacral ligament, bladder, rectal \nand ovarian biopsy samples); \nexocervical swabs\n• Surgical isolation of endo-\nmetriotic lesions; clinical or \nhistological diagnosis\n• HPV detection: exocervical \nswab; tissue biopsy sample \nanalysis by HPV Direct Flow \nCHiP and PCr\n• HPV was detected in 20  \n(n = 20/81; 24.69%) patients \n(9 women with pelvic HPV, \n9 women with vaginal HPV, \nand 2 women with both)\nZullo et al. \n2023 [32]\nObservational, \nprospective, \ncohort study\n457 patients; cervical swabs; \nendometrial and granulosa cell \nsamples collected before or \nduring IVF procedure\n• Endometriosis diagnostic \ncriteria not stated \n• HPV detection: cervical, \nendometrial and granulosa \ncells HPV PCR-based detec-\ntion \n• endometriosis was sig-\nnificantly more frequent in \nhrHPV-positive than in nega-\ntive women (31.6% vs 10.1%; \np < 0.01)\nHPV – human papillomavirus; hrHPV – high-risk HPV; mrHPV – medium-risk HPV; OR – odds ratio; CI – confidence interval; aRP – adjusted prevalence \nratio; US – United States; BLAST – Basic Local Alignment Search Tool; PCR – Polymerase Chain Reaction; PCR-RFLP – Polymerase Chain Reaction-\nRestriction Fragment Length Polymorphism; LGT – lower genital tract; UGT – upper genital tract.\nThe study’s results showed that 6% of lesions in the study group \nand 3.3% in the control group were non-interpretable. Among \nthe interpretable lesions, 88.7% in the study group and 72.4% \nin the control group tested negative for HPV-DNA. Interestingly,  \n7 out of 62 interpretable endometriosis lesions from indepen -\ndent patients (11.3%) tested positive for HPV-DNA. Among these \npositive cases, 71.4% were classified as high-risk subtypes, and \n28.6% as medium-risk subtypes. In the control group, 8 out of \n29 interpretable control tissues (27.5%) were also found to be \nHPV positive. Among these cases, 75% were classified as high-\nrisk subtypes, while 25% were medium-risk subtypes. Notably,  \n1 patient in this group had an HPV 18-positive ovarian endome-\ntriosis lesion, which was also associated with an ovarian adeno-\ncarcinoma in the same ovary, indicating a possible endometrio-\nsis-associated carcinoma. This finding raised significant interest. \nMoreover, a paraffin tissue section from the remaining normal \novary of this patient was tested for HPV-DNA using immunohis-\ntochemistry, and surprisingly, it was found to be HPV-negative, \ncontrasting with the HPV-positive ovarian lesion. Despite these \nobservations, the authors concluded that due to the limited \ntesting of study participants for HPV-DNA, it remains challeng -\ning to definitively ascertain whether persistent HPV infection \nincreases the risk of endometriosis. To gain more conclusive \ninsights, further research involving a larger number of patients \nspecifically tested for HPV-DNA would be required. Neverthe -\nless, the study’s findings suggest that persistent HPV infection, \nparticularly involving high-risk types, within an endometriosis \nlesion may potentially play a role in promoting its transforma-\ntion into a carcinoma.\nIn a study conducted in Denmark by Vestergaard et al., they \ninvestigated the potential involvement of pathogenic viruses, \nincluding HPV, in 52 Danish patients with and without endome-\ntriosis using highly sensitive PCR tests [19]. Samples were col -\nlected from the eutopic endometrium of all 32 women suffering \nfrom endometriosis, and in addition, ectopic endometriotic le-\nsions were obtained from 27 of these patients through excision \nwith scissors or biopsy forceps. The ectopic tissue was sourced \nfrom either one of the ovaries or the peritoneum. 20 women \nwith no indication of endometriosis were included as healthy \ncontrols. In this study, 3 cases with positive HPV were detected. \nAmong the 32 endometriosis patients, only 1 sample (3%) test -\ned positive for HPV-DNA, while HPV was detected in the endo -\nmetrium of 2 women in the control group (10%). The prevalence \nof HPV-DNA did not display a significant difference between the \n2 study groups. Interestingly, no HPV was found in the samples \nobtained from the ectopic group. Considering these findings, \nthe authors concluded that the prevalence of pathogenic dnA \nviruses, including HPV, in the endometrium and endometriosis \nlesions is remarkably low. Consequently, this finding does not \nstrongly support the hypothesis of a viral pathophysiology of \nendometriosis. Nevertheless, they underscored that the possi -\nbility of an infectious causal agent cannot be entirely ruled out \nbased on the presented results. Therefore, further investiga-\ntions in this area are warranted to gain a more comprehensive \nunderstanding of any potential association between viral infec-\ntions and the development of endometriosis.\nIn 2017, Heidarpour et al. conducted a cross-sectional study \nin iran to delve further into the topic, as previous literature pre-\nsented inconclusive results [17]. The study involved 99 patients, \nwith 50 samples of ovarian endometriosis and 49 samples of \novarian tissue from women without endometriosis. The re -\nsearchers utilised PCR to assess the prevalence of high-risk hu -\nman papillomavirus (hrHPV) in these samples. Notably, there \nwere no significant differences between the groups concern-\ning age, marital status or parity. The study’s findings revealed \na noteworthy result: the prevalence of high-risk HPV was sig-\nnificantly higher in patients with endometriosis, with 13 cases \n(26%) compared to 5 cases (10.2%) in patients without endome-\ntriosis. However, the study did have certain limitations, includ -\ning a retrospective design and a lack of access to more detailed \ndata about the studied patients. Additionally, the sample size \nwas relatively small. Despite these limitations, the authors em -\nphasised the necessity for further prospective research on larg-\ner groups of patients, accompanied by thorough clinical analy -\nsis. During laparoscopic surgery, researchers collected samples \nfrom both the upper genital tract (UGT) and lower genital tract \n(LGT) of the participants and analysed them using PCR to detect \nthe presence of HPV and 7 other sexually transmitted infections \n(STIs). Initially, the participants were divided into 2 groups: in -\nfertile patients (n = 25) and fertile controls (n = 35). After analys-\ning the surgical findings, they further divided the participants \ninto an endometriosis group (n = 29) and a non-endometriosis \ncontrol group (n = 31). Among the 60 women studied, 36 (60%) \ntested positive for 13 different HPV types in either the LGT, UGT \nor both. Out of these cases, 7 (53.8%) were low-risk (lr) HPV, and \n6 (46.2%) were high-risk (hr) HPV. Among the HPV-DNA-positive \nwomen, 25 (69.4%) had only hrHPV, 7 (19.4%) had only low risk \nHPV (lrHPV), and 4 (11.1%) had multiple HPV infections.\nRegarding the infertile patients, 15 out of 25 (60%) had HPV-\nDNA, with 13 of them (87%) having hrHPV. Statistically, when \ncomparing UGT sites, infertile patients were significantly more \noften hrHPV positive compared to the fertile control group, with \nan over three-fold increased risk. Interestingly, only hrHPV types \nwere detected in the UGT for both infertile patients and fertile \ncontrols.\n\nA. Sienko et al. • Association of endometriosis with HPV infection\nFamily Medicine & Primary Care Review 2023; 25(4)\n463\nwent laparoscopic surgery for endometriosis [30]. Among these \nparticipants, 20 women (24.69%) were found to be infected \nwith HPV, with low-risk HPV being more prevalent in the study \npopulation. Interestingly, the study results showed that HPV in-\nfection was not significantly associated with the severity of en-\ndometriosis, age, BMI, parity, disease duration since diagnosis, \nuterus size, history of surgery, urinary signs, menstrual status \nor treatment method. When considering the prevalence of HPV \ninfection in the Iranian population, which is estimated to be be-\ntween 7–10%, it is evident that HPV is more common among \npatients with confirmed endometriosis (24.69%) compared to \nthe general population [31]. \nIn 2023, a recent observational, prospective cohort study \nconducted by Zullo et al. presented different conclusions com-\npared to the two previous publications of that year [32]. The \nstudy aimed to assess the prevalence of HPV infection in women \nundergoing in vitro fertilisation (IVF) and its potential effects on \nembryonic development and IVF outcomes. A total of 457 wom-\nen with couple’s infertility, who were candidates for IVF, under-\nwent HR-HPV testing. Out of these participants, 326 underwent \ntheir first IVF cycle and were included in the analysis. Among \nthem, 41 (8.9%) were found to be HPV positive based on cervi-\ncal swab tests. The study found that HPV prevalence was higher \nin younger women and decreased linearly with age. An interest-\ning observation was that among the various causes of infertility, \nendometriosis stood out as being significantly more frequent in \nhrHPV-positive women than in hrHPV-negative women (31.6% \nvs 10.1%). However, no significant difference was observed in \nthe distribution of other causes of infertility between couples \nwith HPV-positive or negative cervical swabs.\nSimilar to the findings presented by Rocha et al., this study \nsupported the observation that HPV can move along the female \ngenital tract and infect the upper genital tract (UGT) in a con -\nsiderable proportion of women who test positive for HPV at the \ncervical level. Additionally, the authors suggested that the hy -\npothesis of an active involvement of HPV in the development \nof endometriosis warrants further investigation. The potential \noncogenic effect of HPV at the endometrial and ovarian levels, \nas discussed in the study by Oppelt et al., also requires further \nscrutiny.\nConsidering the aforementioned studies, it is essential to \nnote the heterogeneity of the presented results, which may \nbe attributed to the diversified research methodologies, the \nrelatively small size of the study groups and the primarily retro-\nspective nature of the research. Out of the 8 reviewed papers, \n3 demonstrated a statistically significant correlation between \nHPV infection and endometriosis, while three others indicated a \nhigher incidence of HPV infection in patients with confirmed en-\ndometriosis, although a significant correlation was not conclu -\nsively established due to the limitations of the research meth-\nodologies and sample sizes. Heidarpour et al., Oppelt et al., \nRocha et al., Matalliotakis et al., Moslehi et al. and Zullo et al. \nreported higher rates of HPV detection in endometriosis lesions, \ncontrasting with Vestergaard et al. and Hong et al., whose stud-\nies did not find such a correlation [17–20, 28–30, 32]. Further -\nmore, a difference was observed in the dominant type of HPV \nserotype in the study populations. Heidarpour et al. and Rocha \net al. found that hrHPV was most common among patients diag-\nnosed with endometriosis, whereas Moleshi et al. showed that \nlrHPV was more prevalent.\nbased on the presented literature review, it is currently chal-\nlenging to scientifically substantiate the hypothesis of a viral ori-\ngin of endometriosis. In none of the studies was a causal rela-\ntionship between the presence of HPV-DNA and endometriosis \ndemonstrated. Based on the available data, it cannot be ruled \nout that there is another factor contributing to the presence of \nboth. \nHowever, it is noteworthy that there are some studies which \nsuggest that persistent HPV infection of the female genital tract, \nIn relation to endometriosis patients, 24 out of 29 (82.8%) \nwere HPV-DNA positive, whereas in the non-endometriosis con-\ntrol group, HPV-DNA was detected only in 12 out of 31 (38.7%) \ncases, resulting in an increased risk of infection higher than six-\nfold for the endometriosis patients. Furthermore, in patients \nwith endometriosis, hrHPV was present both in the LGT and \nUGT sites, with an over eight-fold increased risk for the former \nand over three-fold increased risk for the latter. Similarly to the \nprevious cases, only hrHPV types were detected in the UGT, \nregardless of the group. This study marked the first time that \na continuum of hrHPV infection was observed from the LGT to \nthe UGT. Additionally, it revealed an association between hrHPV \ninfection in the UGT with infertility, particularly with endometri-\nosis. Interestingly, no association with either endometriosis or \ninfertility was observed among the other 7 STIs studied. More -\nover, the study found that only infertile and endometriosis pa-\ntients had hrHPV detected in the ovaries, while their respective \ncontrol groups did not show such findings.\nThis topic has continued to captivate scientists in recent \nyears. In 2021, Matalliotakis et al. published a retrospective, \nepidemiological and noncomparative study focusing on cervi-\ncal endometriosis [28]. Among 860 records of women with \nendometriosis who underwent surgical treatment, 27 were \ndiagnosed with cervical endometriosis based on tissue biopsy. \nThrough retrospective analysis of these 27 cases, a compelling \nrelationship between cervical endometriosis and cervical in -\ntraepithelial neoplasia (CIN) emerged, with 19 out of 27 cases \n(70%) showing a coexistence with CIN. Furthermore, the study \nconfirmed a high prevalence of HPV in this group, as HPV was \ndetected in 16 out of 27 samples with cervical endometriosis \n(59.2%). The study also revealed the coexistence of malignant \ngynaecological pathologies in 7 cases, comprising 2 with cervi-\ncal cancer (7.4%), 2 with endometrial cancer (7.4%) and 3 with \novarian cancer (11.1%). However, it is important to note that the \nfocus of interest in this study was not solely on the presence of \nHPV-DNA but rather the cervical dysplasia resulting from it and \nthe role of a coexistence between this pathology and cervical \nendometriosis. Based on the results, the authors concluded that \nwhile the pathophysiology and genetics of cervical dysplasia are \nwell defined, further research is necessary to establish a robust \nassociation between cervical endometriosis and gynaecological \npremalignant and malignant pathology. The findings highlight \nthe importance of continued investigation to gain a more com-\nprehensive understanding of the intricate relationship between \ncervical endometriosis, HPV infection and the development of \ngynaecological malignancies.\nIn 2023, Hong et al. conducted the first national representa-\ntive survey in the United States to investigate the prevalence of \ngenital human papillomavirus (HPV) in women with endome-\ntriosis [29]. The study included 1,768 women, providing insights \ninto a broader population of females. Data was collected be-\ntween 2003 and 2006, a period preceding the approval of an \nHPV vaccination by the US Food and Drug Administration (FDA). \nAmong the study participants, 129 women reported physician-\ndiagnosed endometriosis, accounting for 9.5% (95% CI 7.3–12.3) \nof the group. HPV and hrHPV were diagnosed in 57 (36.9%) and \n31 (19.8%) patients with endometriosis, respectively. Despite \nthese findings, the study did not reveal a significant association \nbetween the prevalence of high-risk HPV and the diagnosis of \nendometriosis, even after accounting for multiple sociodemo -\ngraphic factors. Interestingly, the authors also observed that the \nassociation between endometriosis and HPV infection varied \ndepending on access to health care. For participants without \nhealth insurance coverage, the prevalence of any HPV infection \nin women with endometriosis was higher than in those without \nendometriosis. Conversely, in a subgroup with health insurance, \na statistically significant lower prevalence of any HPV infection \nwas observed in women with endometriosis.\nIn 2023, another noteworthy cross-sectional study was con-\nducted by Moslehi et al. in Iran, involving 81 women who under-\n\nA. Sienko et al. • Association of endometriosis with HPV infection\nFamily Medicine & Primary Care Review 2023; 25(4)\n464\nSource of funding: This work was funded from the authors’ own resources.\nConflicts of interest: The authors declare no conflicts of interest.\nReferences\n1. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet 2021; \n397(10276): 839–852.\n2. Taylor HS, Adamson GD, Diamond MP , et al. An evidence-based approach to assessing surgical versus clinical diagnosis of symptomatic \nendometriosis. Int J Gynecol Obstet 2018; 142(2): 131–142.\n3. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet \nGynecol 1927; 14: 422–469.\n4. Bulun SE, Yilmaz BD, Sison C, et al. Endometriosis. Endocr Rev 2019; 40(4): 1048–1079.\n5. Chen LC, Hsu JW, Huang KL, et al. Risk of developing major depression and anxiety disorders among women with endometriosis:  \nA longitudinal follow-up study. J Affect Disord 2016; 190: 282–285.\n6. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science 2005; 308(5728): 1587–1589.\n7. Simoens S, Dunselman G, Dirksen C, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and \ntreated in referral centres. Human Rep 2012; 27(5): 1292–1299.\n8. Rei C, Williams T, Feloney M. Endometriosis in a Man as a Rare Source of Abdominal Pain: A Case Report and Review of the Literature. \nCase Rep Obstet Gynecol 2018; 2018: 2083121.\n9. Matsuura K, Ohtake H, Katabuchi H, et al. Coelomic metaplasia theory of endometriosis: evidence from in vivo studies and an in vitro \nexperimental model. Gynecol Obstet Invest 1999; 47(Suppl. 1): 18–20.\n10. Dmowski WP , Braun DP . Immunology of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004; 18(2): 245–263.\n11. Koninckx PR, Ussia A, Adamyan L, et al. Pathogenesis of endometriosis: the genetic/epigenetic theory. Fertil Steril 2019; 111(2): 327–\n340.\n12. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012; 98(3): 511–519.\n13. Kobayashi H, Higashiura Y , Shigetomi H, et al. Pathogenesis of endometriosis: The role of initial infection and subsequent sterile inflam-\nmation (Review). Mol Med Rep 2014; 9(1): 9–15.\n14. Khan KN, Fujishita A, Hiraki K, et al. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol 2018; 17(2): \n125–133.\n15. Dunne EF, Park IU. HPV and HPV-associated diseases. Infect Dis Clin North Am 2013; 27(4): 765–778.\n16. Ho GY , Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; \n338(7): 423–428.\n17. Heidarpour M, Derakhshan M, Derakhshan-Horeh M, et al. Prevalence of high-risk human papillomavirus infection in women with \novarian endometriosis. J Obstet Gynaecol Res 2017; 43(1): 135–139.\n18. Rocha RM, Souza RP , Gimenes F, et al. The high-risk human papillomavirus continuum along the female reproductive tract and its rela-\ntionship to infertility and endometriosis. Reprod Biomed Online 2019; 38(6): 926–937.\n19. Vestergaard AL, Knudsen UB, Munk T, et al. Low prevalence of DNA viruses in the human endometrium and endometriosis. Arch Virol \n2010; 155(5): 695–703.\n20. Oppelt P , Renner SP , Strick R, et al. Correlation of high-risk human papilloma viruses but not of herpes viruses or Chlamydia trachomatis \nwith endometriosis lesions. Fertil Steril 2010; 93(6): 1778–1786.\n21. Malhotra N, Karmakar D, Tripathi V, et al. Correlation of angiogenic cytokines-leptin and IL-8 in stage, type and presentation of endo-\nmetriosis. Gynecol Endocrinol 2012; 28(3): 224–227.\n22. Plummer M, Schiffman M, Castle PE, et al. A 2-year prospective study of human papillomavirus persistence among women with  \na cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion.  J Infect \nDis 2007; 195(11): 1582–1589.\n23. Hausen H, zur. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000; \n92(9): 690–698.\n24. Watanabe A, Taniguchi F, Izawa M, et al. The role of survivin in the resistance of endometriotic stromal cells to drug-induced apoptosis. \nHum Reprod 2009; 24(12): 3172–3179.\n25. Bulun SE. Endometriosis. N Engl J Med 2009; 360(3): 268–279.\n26. Melin A, Sparén P , Bergqvist A. The risk of cancer and the role of parity among women with endometriosis. Hum Reprod 2007; 22(11): \n3021–3026.\n27. Kim CJ, Um SJ, Kim TY , et al. Regulation of cell growth and HPV genes by exogenous estrogen in cervical cancer cells. Int J Gynecol \nCancer 2000; 10(2): 157–164.\n28. Matalliotakis M, Matalliotaki C, Zervou MI, et al. Coexistence of cervical endometriosis with premalignant and malignant gynecological \npathologies: report on a series of 27 cases. Women Health 2021; 61(9): 896–901.\n29. Hong YS, Park J, Kim H. Association of endometriosis with genital human papillomavirus infection in US women: a national population-\nbased study. Sci Rep 2023; 13(1): 8020.\n30. Moslehi Z, Derakhshan R, Chaichian S, et al. Correlation of High-Risk Human Papilloma Virus with Deep Endometriosis: A Cross-Section-\nal Study. Biomed Res Int 2023; 2023: 6793898.\n31. Jamdar F, Farzaneh F, Navidpour F, et al. Prevalence of human papillomavirus infection among Iranian women using COBAS HPV DNA \ntesting. Infect Agent Cancer 2018; 13: 6.\nparticularly with hrHPV, may predispose the invasive capacity of \nendometrial tissue, leading to the formation of endometrial le-\nsions as a possible effect of retrograde menstruation [32].\nAll cited authors agree that further research should be \nconducted to delve deeper into this matter and determine the \npotential role of HPV infection in the formation of endometri-\nal lesions. To establish a more comprehensive understanding, \nlarger and more well-designed studies are required, incorpo -\nrating prospective methodologies and considering potential \nconfounding factors. Until then, the exact relationship between \nHPV and endometriosis remains an intriguing area for ongoing \ninvestigation.\n\nA. Sienko et al. • Association of endometriosis with HPV infection\nFamily Medicine & Primary Care Review 2023; 25(4)\n465\n32. Zullo F, Fiano V, Gillio-Tos A, et al. Human papillomavirus infection in women undergoing in-vitro fertilization: effects on embryo devel-\nopment kinetics and live birth rate. Reprod Biol Endocrinol 2023; 21(1): 39.\nTables: 1\nFigures: 1\nReferences: 32\nReceived: 21.07.2023\nReviewed: 10.08.2023\nAccepted: 17.08.2023\nAddress for correspondence:\nAleksandra Urban, MD\nII Katedra i Klinika Położnictwa i Ginekologii \nWarszawski Uniwersytet Medyczny\nul. Karowa 2 \n00-315 Warszawa\nTel.: +48 694961929\nE-mail: aleksandra1mar@gmail.com","source_license":"CC0","license_restricted":false}