{"paper_id":"c47dd86a-9afb-47ec-97e3-dc57a12d23d2","body_text":"Vol.:(0123456789)1 3\nCurrent Obstetrics and Gynecology Reports (2022) 11:95–102 \nhttps://doi.org/10.1007/s13669-022-00326-7\nUTERINE FIBROIDS AND ENDOMETRIAL LESIONS (T. TULANDI, SECTION EDITOR)\nMechanisms and Pathogenesis of Adenomyosis\nMargherita Rossi1 · Silvia Vannuccini1 · Tommaso Capezzuoli1 · Massimiliano Fambrini1 · Valentina Vannuzzi1 · \nChiara Donati1 · Felice Petraglia1\nAccepted: 3 February 2022 / Published online: 18 March 2022 \n© The Author(s) 2022, corrected publication 2022\nAbstract\nPurpose of the Review The purpose of this review is to provide a synopsis of all the mechanisms involved in the pathogenesis of  \nadenomyosis. It will summarize recent advances in the field, discussing current controversies, and considering potential future directions.\nRecent Findings Adenomyosis pathogenesis is still a topic under investigation, however advancements in the understand-\ning of disease development and mechanisms have been made. New data coming from new next generation sequencing-based \nstudies and more-in-depth acquisitions on sex hormones imbalance, neuroangiogenesis, inflammation, fibrosis and cell \nproliferation have been obtained.\nSummary Adenomyosis is a uterine disorder that affects women of reproductive age, characterized by a benign invasion of \nthe endometrium basalis (glands and stroma) within the myometrium.\nSo far, three theories for the pathophysiology of adenomyosis have been proposed:\n1. An invagination of the endometrial basalis into the myometrium by tissue injury and repair.\n2. The development from adult stem cells or displaced embryonic müllerian remnants.\n3. An “invasion from outside to inside”.\nIn order to invade and develop, endometrial cells require a series of pathogenetic mechanisms which drive to adenomyosis. \nAltered sex steroids hormones receptors may be the primary event which causes increased endometrial cell proliferations \nand differentiation from epithelial to mesenchymal cells. Once invaded the myometrium, an inflammatory reaction is dis-\nplayed, probably driven by local immune changes. The processes of neuroangiogenesis and fibrosis are also involved in the \nadenomyosis development and may explain some of the associated clinical symptoms (dysmenorrhea, abnormal uterine \nbleeding, and infertility).\nKeywords Abnormal uterine bleeding · Adenomyosis · Endometriosis · Pathogenesis of adenomyosis · Dysmenorrhea · \nEndometrial cells differentiation · Inflammation · Infertility\nThis article is part of the Topical Collection on Uterine Fibroids \nand Endometrial Lesions\n * Felice Petraglia \n felice.petraglia@unifi.it\n1 Obstetrics and Gynecology and Molecular Biology, \nDepartment of Experimental, Clinical and Biomedical \nSciences, Careggi University Hospital, University \nof Florence, Florence, Italy\nIntroduction\nIn 1860, Rokitansky was the first to recognize adenomyosis \nand to acknowledge the presence of endometrial glands and \nstromal cells within the myometrium (adenomyosis) and \noutside the uterine cavity (endometriosis). He denominated \nthe two conditions respectively “endometriosis interna” and \n“endometriosis externa”. The first to use the term “adeno-\nmyosis” was Frankl [1], who  used this compound word in \n1925 (it is derived from the Greek phrases (αδέvας), gland, \nand mís (μυς), muscle) to describe a pathological disease of \nthe muscular uterine tissue involving endometrial glands.\nAdenomyosis is a benign estrogen-dependent uterine dis-\norder that affects women of reproductive age. It is defined \nby the presence of endometrium basalis (glands and stroma) \ninfiltration within the myometrium through an altered junc-\ntional zone (JZ), associated with myometrial hypertrophy/\nhyperplasia and fibrosis [1 ]. Several classifications have \nbeen developed and a number are still under development \n\n96 Current Obstetrics and Gynecology Reports (2022) 11:95–102\n1 3\nto describe adenomyosis by using histological or imaging \ncriteria [2]. However, the most  currently used classification \ndescribes three different phenotypes of adenomyosis: dif-\nfuse, when glands and stroma are dispersed throughout the \nmyometrium; focal, when a nodular adenomyosis localiza-\ntion is identified, and adenomyoma (a cystic adenomyotic \nlesion) [3].\nAside from the diverse histological patterns, patients with \nadenomyosis suffer from dysmenorrhea, abnormal uterine \nbleeding, and infertility [4••]. In the past, adenomyosis was \ndiagnosed predominantly in multiparous women, whereas \nnowadays it is identified also in young women of reproduc-\ntive age due to the enhanced imaging techniques [4••, 5].\nIn order to explain the migration of endometrial cells \nand development of adenomyotic lesions within the myo-\nmetrium, at least three theories are currently debated: a — \n“invasion from inside”, b — metaplasia of displaced embry-\nonic pluripotent Mullerian remnants or adult stem cells, or \nc — “invasion from outside” [6 , 7••].\nIn order to invade the myometrium, endometrial cells \nundergo a series of pathogenic processes which involve \nendocrine (gonadal sex steroid hormones), immune (inflam-\nmation), vascular (neoangiogenesis), and neuronal (neuro-\ngenesis) mechanisms [8, 9].\nTheories on the Origin of Adenomyosis\nInvagination of the Endometrial Basalis \ninto the Myometrium\nContractions of the myometrium itself and the resultant \ntrauma to the endometrial myometrial junction zone (JZ), a \nhighly specialized hormone-responsive layer of the uterine \narchitecture located in the inner third of the myometrium, may \nlead to the establishment of adenomyosis through invagina-\ntion of the endometrium basalis into the myometrium [7••].\nThe TIAR theory (tissue injury and repair) was at the \nbase of the Leyendecker’s “invagination theory” [8]. More \nspecifically, in reaction to an injury/trauma, the TIAR sys-\ntem is activated, more estrogen is released locally due to \nlocal paracrine activity, boosting uterine contractility. A \nvicious loop is maintained, characterized by an increased \nrelease of estrogens, auto-traumatization and wound heal -\ning, which promotes inflammation and again a production \nof local estradiol [8, 9].\nBesides, a new theory, named EMID (endometrial-  \nmyometrial interface disruption) has been proposed. This theory  \nrevises the tissue injury and healing theory, and claims that \nEMID caused by uterine surgeries might lead to a “iatro-\ngenic” adenomyosis later in life [9, 10]. Indeed, a mechani-\ncal or thermal (as in electrocoagulation) elicitation of EMID \nis possible. Both modalities produce tissue damage, which \nstimulates substance P secretion that acts like an immune \nmodulator, and activates the hypothalamic–pituitary–adrenal \naxis, resulting in an increase in catecholamine release, such \nas adrenaline/noradrenaline, which in turn may decrease \ncell-mediated immunity. Moreover, it was demonstrated \nthat EMID, whether mechanically or thermally produced, \nmay cause adenomyosis in mice, and the chance of inducing \nadenomyosis appears to be dependent on the severity of the \nEMID [10]. The EMID hypothesis includes epithelial mes-\nenchymal transition, recruitment of bone-marrow-derived \nstem cells, and enhanced survival of endometrial cells dis-\npersed and displaced due to iatrogenic procedures, in addi-\ntion to hypoxia at the wounding site.\nMore crucially from a clinical point of view, considering \nthe EMID hypothesis, specific perioperative therapies may \nminimize the development of adenomyosis [11].\nDevelopment from Adult Stem Cells\nAdenomyotic lesions may also evolve indipendently and de \nnovo from:\na) Metaplasia of misplaced embryonic pluripotent Muller-\nian remnants in the myometrium. The Mullerian ducts \nare fundamental embryological structures that develop \ninto the female uterine tract throughout fetal life. These \nducts are constituted of surface epithelium and urogeni-\ntal ridge mesenchyme, which can develop into endome-\ntrial glands and stroma.\nb) Multipotent adult stem cells differentiation (EnSCs) \nresiding within the myometrium [9 , 12]. These stem \ncells are hypothesized to reside within cell niches in \nthe endometrium basalis to ensure cells regeneration \nand replacement in healthy endometrium. However, \nthe presence of these cells may also promote unregu-\nlated proliferation that can extend beyond the endo-\nmetrium.\nIndeed, the capacity of a little portion of endometrium to \nreestablish the full functional layer is guaranteed by progeni-\ntor cells within the basal layer, where they restore glands, \nendometrial vasculature and stroma [12]. Menstrual blood-\nderived mesenchymal stem cells (MenSCs) may be displaced \nwithin the myometrium establishing de novo adenomyotic \nfoci in a similar way how endometrial glands and stroma \nare formed [7••].\nInvasion from Outside to Inside\nAdult endometrial cells may be displaced into the myo -\nmetrium as a result of the phenomenon of retrograde men-\nstruation and the ability of ectopic endometrial cells to \nmigrate and invade pelvic peritoneum. These cells seem \nto have the capability to invade the pelvic organs as well \n\n97Current Obstetrics and Gynecology Reports (2022) 11:95–102 \n1 3\nas the uterine walls and develop intra-myometrial endome -\ntrial implants, according to “from outside to inside inva-\nsion” theory [4••, 13]. The strong association between the \nposterior focal adenomyosis and deep infiltrating endome-\ntriosis nodules in the posterior compartment in endome -\ntriosis/adenomyosis patients supports the hypothesis [13] \nof a “from outside to inside invasion”, which refers to the \ndisplacement of endometrial cells into the myometrium \nfrom endometriosis lesions [13, 14].\nPathogenetic Mechanisms\nSeveral mechanisms are involved in the pathogenesis of \nadenomyosis: impaired gonadal sex steroids hormones \nreceptors function,  altered cell proliferation and differ -\nentiation, inflammatory reaction, processes of neuroan-\ngiogenesis and fibrosis (Fig.  1).\nThe Role of Ovarian Sex Steroid Hormones\nEstrogens and progesterone are the key regulators of healthy \nendometrium physiology to boost a regular menstrual cycle \nand create the perfect environment for embryo implantation.\nAdenomyosis is promoted by an imbalance between \nestrogens and progesterone signaling in women during \nreproductive life [5 , 7••, 15]. A high local production \nof estrogen, with normal peripheral levels of estradiol, \nhas been shown in adenomyotic lesions, due to the high \nexpression of aromatase [16, 17]. In fact, also high levels \nof estradiol in menstrual blood in comparison to normal \nserum levels have been shown in women with adenomy -\nosis [7 ••, 17]. Furthermore, the gene polymorphism of \naromatase cytochrome P450 has been found in the eutopic \nendometrium of patients with adenomyosis, and it is \nassociated with a high local production of estrogen [18]. \nFig. 1  Outline of all the pathogenetic mechanisms of adenomyosis that will be treated in this review \n\n98 Current Obstetrics and Gynecology Reports (2022) 11:95–102\n1 3\nPolymorphisms of the estrogen receptor alpha (ERα) gene \nare also linked to an increased incidence of adenomyosis \nwith a greater ER-beta expression in the myometrium of \nadenomyotic uteri, contributing to myometrial hyperplasia \n[15]. Furthermore, the modulation of 17b-hydroxysteroid \ndehydrogenase type 2 (an essential enzyme for the deac-\ntivation of estradiol to estrone) in the eutopic endome-\ntrium of women with adenomyosis differs compared to \nnon-affected ones, as mRNA and 17bHSD2 activity are \nfour- to six-fold higher in adenomyosis [17].\nThe increased estrogen activity stimulates the prolif-\nerative response, leading to changes in the expression of \nvarious other genes and may be related to the increased \nanti-apoptotic activity of the basalis, promoting the invagi-\nnation process and the ‘spreading” of adenomyosis into \nthe myometrium. Altered contractions stimulate the TIAR \nmechanism, resulting in enhanced estradiol production \ncreating a loop that induces the invasion of the endome-\ntrial basalis into the myometrium and the formation of \nadenomyotic lesions [5 , 7••].\nThe imbalance between estrogens and progesterone \nsignaling is also caused by a decrease of progesterone \nactivity, as suggested by the evidence that stromal cells of \nthe functionalis and basalis endometrium of women with \nadenomyosis display a reduced immunoreactivity for iso-\nform B of P receptor (PR-B), causing a loss of P effects \n[15]. As a result, estrogen-driven proliferative effects on \nthe endometrium are not sufficiently counteracted by P \nduring the secretory phase of the cycle, strengthening \nabnormal endometrial growth.\nIn addition, in ectopic endometrium, all three DNA Meth-\nyltransferases (DNMTs) are abnormally expressed, causing \nepigenetic changes. Disrupting either DNMT1 or DNMT3B \nalone seems to have a little effect on gene-specific methyla-\ntion and related gene silencing in vitro. When both enzymes  \nare disrupted, methyltransferase activity is almost inhib-\nited, resulting in widespread chromosomal demethylation. \nIn adenomyosis, immunoreactivity to DNMTs differs from \nthat of normal endometrium, opening the scenario  that \nadenomyosis is an epigenetic disorder [19]. These enzymes \nand several other mechanisms seem to be involved in the \nepigenetic regulation of ERs and PRs in patients with endo-\nmetriosis, such as miRNA, transcriptional factors like GATA \nfamily, lncRNA [20]. However, additional studies are needed \nto state if these mechanisms are substantially involved  \nalso in adenomyosis.\nNew next generation sequencing (NGS)-based studies are \nshowing that KRAS mutations, a cancer-associated gene, are \nmore likely to be found in patients with adenomyosis and co-\noccurring endometriosis, causing inadequate PR expression \n[21]. KRAS activating mutations trigger particular pathways \nto enhance cell survival and proliferation, and are linked to \nprogesterone resistance in adenomyosis [22••].\nCell Proliferation and Differentiation: \nEpithelial‑to‑Mesenchimal Transition (EMT)\nThe development of adenomyosis is related to the endome-\ntrial cells invasiveness of myometrium, and the epithelial-to- \nmesenchymal transition (EMT) is the one of the most \naccepted mechanism to support the changes undergoing \nectopic endometrial cells. Epithelial cells leave their natu -\nral locus by detaching themselves from neighboring cells, \nchange shape and migrate into the extracellular matrix of \nother tissues. This process is the mechanism by which cancer \ncells infiltrate adjacent tissues. The EMT and a dysregulated \nimmunological response are involved in the development of \nadenomyosis [23]. An overexpression of the EMT markers \n(fibronectin, n-cadherin, vimentin), loss of E-cadherin, loss \nof apical–basal cell polarity, a decrease in tight junction pro-\nteins and cytokeratin lead to a mesenchymal cell phenotype \nwith the ability of endometrial cells to migrate and invade.\nThe mesenchymal phenotype is necessary to the cells \nto leave the epithelium and migrate, giving them a cancer-\nlike phenotype and the opportunity to induce the disease. \nThe ETM mechanisms are activated by an increased ER \nexpression, downregulation of PRs and by platelet activa-\ntion, in conjunction with a chronic hyperperistaltic activity \n[5, 9, 22••]. The platelet activation leads to hypoxia and an \nincrease in the biosynthesis of estrogens in patients with \nadenomyosis, making possible the phenotypic change of the \ncell [24, 25].\nIncreased expression of Talin 1 mRNA levels has been \nlinked to adenomyosis [26, 27]. Talin 1 is involved in can-\ncerogenesis and in the activation of the EMT mechanism. \nTalin1, via activation of the canonical wnt/-catenin pathway, \nplays a role in inducing both EMT and increased migration \nand invasiveness in adenomyotic cells [26].\nA comparison of proliferative endometrial transcriptomes \nfrom women with and without adenomyosis identified 140 \nupregulated and 884 downregulated genes in samples from \nthose affected, as well as microRNAs of unclear impor -\ntance. In particular, many miRNAs (like miR-124-3p or \nmiR-145-5p) may have a role in enhancing the migration \nand epithelial-stromal transformation of endometrial stromal \ncells extracted from eutopic endometrium [28, 29].\nInflammation and Immunological Changes\nNowadays, adenomyosis is considered as a chronic inflam-\nmatory disease characterized by abundant inflammatory \nmediators both into adenomyotic lesions and in the perito-\nneal fluid [6, 8, 9, 11].\nThe relevant contribution of COX-2 and prostaglandin \n(PG) pathway in the pathogenesis of adenomyosis has been \nwidely supported. In mice with experimental adenomyosis, \nthe degree of muscularis infiltration in the endometrium was \n\n99Current Obstetrics and Gynecology Reports (2022) 11:95–102 \n1 3\nreduced after the treatment of celecoxib (a selective inhibi-\ntor of COX-2), thus suggesting a major role of COX2 in the \ndisease [30]. An increased expression of COX2 and PGs \nis observed in the presence of corticotropin releasing hor -\nmone (CRH) and urocortin (UCN), two potent inflammatory \npeptides, whose mRNA expression is increased in patients \nwith adenomyosis [31]. In addition, in adenomyotic uteri  \nan imbalance between pro-inflammatory and anti-inflammatory  \ncytokines was shown, as well as other immunological \nmarkers, with an increase in the levels of a number of pro-\ninflammatory factors (IL1b, IL6, IFNa, IFNc, TNFa, and \nothers) and anti-inflammatory signals (IL-10, TGF-β) [11, \n32]. This mechanism may produce a disrupted symmetry \nbetween pro-inflammatory and anti-inflammatory signals, \nlinked with platelet activation that could consequently favors \nendometrial cell migration into the myometrium and EMT \nactivation [25].\nMoreover, in some recent studies, cannabinoids (CB), \nmolecules that play a role in inflammation and in immu-\nnomodulation, have been taken into consideration. Two CB \nreceptors, CB1 and CB2, are abnormally expressed in the \nendometrium and myometrium of patients with adenomyo-\nsis, suggesting a possible role of these molecules [33, 34].\nAngiogenesis and Neurogenesis\nAngiogenesis is a mechanism that involves the formation of \nnew capillaries from pre-existing blood vessels and occurs \nphysiologically in the proliferative phase of the menstrual \ncycle [35]. It was initially identified in several tumors, in \nwhich cells mutate and begin to produce angiogenic factors, \nthus implementing the angiogenic switch. An abnormal and \nintensified vascularization has been observed also in aden-\nomyosis and, in this regard, estrogens promote cell mobi -\nlization and microvascular integration [35]. An increased \nneoangiogenesis in adenomyosis is confirmed by increased \nmicrovessel density both in ectopic and eutopic endome -\ntrium [36].\nVascular endothelial growth factor (VEGF), a strong \nendothelial cell mitogen highly secreted by endometrial \nepithelial, stromal, and perivascular cells in adenomyosis, \nis involved in this mechanism [37, 38]. It is a critical factor \nto regenerate the endometrial layer after menstruation but \nit has  been shown to be over-expressed in patients with \nadenomyosis [35, 37, 38]. Hypoxia plays a direct role in \nincreasing VEGF levels, leading to an angiogenesis activa-\ntion in adenomyotic lesions and to abnormal uterine bleed-\ning as a symptom. In particular, VEGF expression seems to \nbe caused by an overexpression of hypoxia inducible factor \n(HIF-1) action in response to hypoxic stimuli [39].\nTwo other growth factors are actively involved in neo-\nangiogenesis, follistatin and activin A, members of TGF-β \nfamily. They act as proangiogenic factors in adenomyosis, \npromoting the creation of new capillaries and increasing the \nsurface of pre-existing capillaries when compared to con-\ntrols. In particular, activin A increases the production of \nVEGF by endometrial stromal cells, modifying the vascular-\nization and leading to the creation of new capillaries [22 ••, \n31]. The mRNA expression of follistatin and activin type \nII receptors is also increased in adenomyotic nodules [31].\nNeurogenesis also appears to be dysregulated in patients \nwith adenomyosis. It is the process by which a coordinated \ngrowth of nerves occurs, regulated by estrogen, by immune \nmediators and other factors [5 , 7••]. In fact, adenomyotic \ntissues express high levels of neurogenic factors, such as \nnerve growth factors (NGF), which regulates the secre-\ntion of inflammatory factors, contributing to dysmenorrhea \nand dyspareunia [40]. NGF production may be induced by \nhyperestrogenism itself, and it may cause mast cell growth \nand degranulation, producing inflammatory mediators. This \nleads to the production of peripheral nociceptors, increas-\ning the perception of pain [39]. Conversely, inflammatory \nmediators, IL-1, TNF-B, largely increase NGF levels, sup-\nporting a connection between inflammatory and neurogenic \npathways [40].\nFibrosis\nFibrosis is another mechanism involved in the pathogenesis \nof adenomyosis [7 ••, 11, 41]. The stiffness of the lesion \nappears to be related with the amount of fibrosis and with \nthe intensity of painful symptoms in patients with adeno-\nmyosis [42].\nSeveral factors may induce fibrosis in adenomyotic \nlesions. TGF-β family signaling modulates smooth muscle \nmetaplasia and fibrosis, by acting via a Smad2/3-dependent  \nsignaling pathway. This mechanism gives the cells the \nability to breakdown the ECM, facilitating their invasive-\nness throughout the myometrium gaining migratory fea-\ntures, such as loss of cell-cell attachment [ 43]. Myostatin \nand activin A are two TGF-β family members that control \nmyometrial cell growth and promote muscle development. \nMyostatin is abundantly expressed in adenomyotic tissues \nand may be implicated, for this reason, in the hyperplasia of \nmyometrial cells surrounding the adenomyotic lesions. An \nincreased expression of these molecules are also observed \nin eutopic endometrium of patients with adenomyosis and \nin adenomyotic tissues supporting their involvement in the \ndisease [44, 45].\nMoreover, an upregulation of nuclear factor 2 (Nrf2) \nmay cause intramyometrial migration of endometrial \nimplants via MMP-9, which is involved in extracellular \nmatrix breakdown. Other MMPs, such as MMP2 and \nMMP3, are also increased in the eutopic endometrium \nof adenomyosis patients, driving myometrial invasion by \nmyometrial bundle cohesion loss. Also, Lysil Oxidase \n\n100 Current Obstetrics and Gynecology Reports (2022) 11:95–102\n1 3\n(LOX), an amine oxidase involved in the synthesis of \nconnective tissue matrices, is involved in the myometrial \ninvasion of endometrial cells because its downregulation \nin adenomyotic lesions results in a lower rigid ECM [28].\nFrom a clinical point of view, transvaginal elastosonog-\nraphy seems to be one of the options to assess the stiffness \nof adenomyosis lesions, hence their fibrotic nature [46]. \nHigher lesional stiffness appears to be associated with \nreduced PR expression, suggesting that those patients may \nbe potentially less likely to respond to progestin therapy \n[46].\nConclusions\nThe understanding of the pathogenetic mechanisms of \nadenomyosis may open new perspectives in developing \nnew tools for the diagnosis and treatment, toward a more \nand more personalized medicine. Dysmenorrhea, abnor -\nmal uterine bleeding and subfertility are linked to different \nadenomyosis phenotypes and diverse underlying pathoge-\nnetic mechanisms [5 , 7••, 47].\nDysmenorrhea seems to be linked to the amount of \nglandular tissue within the myometrium and the number \nof lesions foci. The degree of dysmenorrhea seems to \nbe also linked to the expression of DNA Methyltrans-\nferases 3B opening the hypothesis that adenomyosis \nis an epigenetic disorder. [48]. Furthermore, women \nwith adenomyosis-related menstrual pain have highly \nexpressed markers of neurogenesis [49], suggesting that \nthe increased extent of the local innervation triggers the \npain symptoms [49].\nAUB heavy menstrual bleeding is explained by an \nincreased angiogenesis, whereas infertility seems to be \nrelated to a focal adenomyosis phenotype, along with \nendometrial abnormalities and altered decidualization \nprocess [ 50, 51]. Further studies are needed to have a \nbetter comprehension of all the mechanism involved in \nthis disease, leading to a more precise diagnosis and \ntreatment.\nFunding Open access funding provided by Università degli Studi di \nFirenze within the CRUI-CARE Agreement.\nData Availability To review all information on pathogenic pathways of \nadenomyosis development and clinical presentation, a PubMed search \nof the literature from 1950 to January 2022 was conducted. All relevant \npublications were evaluated, along with their reference lists, to see if \nthere were any further research that might be included.\nCompliance with Ethical Standards \nConflict of Interest The authors declare that they have no conflict of \ninterest.\nHuman and Animal Rights and Informed Consent This article does not \ncontain any studies with human or animal subjects performed by any \nof the authors.\nOpen Access This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article's Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article's Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a \ncopy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\nReferences\nPapers of particular interest, published recently, have \nbeen highlighted as:  \n•• Of major importance\n 1. Benagiano G, Brosens I. History of adenomyosis. Best Pract Res \nClin Obstet Gynaecol. 2006;20(4):449–63.\n 2. Munro MG. Uterine polyps, adenomyosis, leiomyomas, and \nendometrial receptivity. Fertil Steril. 2019;111(4):629–40. \nAvailable from: https:// doi. org/ 10. 1016/j. fertn stert. 2019. 02. 008.\n 3. Robbins. Student Consult [Internet]. 2015;1–1023. 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