Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis

Where histology used the presence of glands and/or stroma in the myometrium as pathognomonic for adenomyosis, imaging uses the appearance of the myometrium, the presence of striations, related to the presence of endometrial tissue within the myometrium, the presence of intramyometrial cystic structures and the size and asymmetry of the uterus to identify adenomyosis. Preliminary reports show a good correlation between the features detected by imaging and the histological findings. Symptoms associated with adenomyosis are abnormal uterine bleeding, pelvic pain (dysmenorrhea, chronic pelvic pain, dyspareunia), and impaired reproduction. However a high incidence of existing comorbidity like fibroids and endometriosis makes it difficult to attribute a specific pathognomonic symptom to adenomyosis. Heterogeneity in the reported pregnancy rates after assisted reproduction is due to the use of different ovarian stimulation protocols and absence of a correct description of the adenomyotic pathology. Current efforts to classify the disease contributed a lot in elucidated the potential characteristics that a classification system should be relied on. The need for a comprehensive, user friendly, and clear categorization of adenomyosis including the pattern, location, histological variants, and the myometrial zone seems to be an urgent need. With the uterus as a possible unifying link between adenomyosis and endometriosis, exploration of the uterus should not only be restricted to the hysteroscopic exploration of the uterine cavity but in a fusion with ultrasound. Where histology used the presence of glands and/or stroma in the myometrium as pathognomonic for adenomyosis, imaging uses the appearance of the myometrium, the presence of striations, related to the presence of endometrial tissue within the myometrium, the presence of intramyometrial cystic structures and the size and asymmetry of the uterus to identify adenomyosis. Preliminary reports show a good correlation between the features detected by imaging and the histological findings. Symptoms associated with adenomyosis are abnormal uterine bleeding, pelvic pain (dysmenorrhea, chronic pelvic pain, dyspareunia), and impaired reproduction. However a high incidence of existing comorbidity like fibroids and endometriosis makes it difficult to attribute a specific pathognomonic symptom to adenomyosis. Heterogeneity in the reported pregnancy rates after assisted reproduction is due to the use of different ovarian stimulation protocols and absence of a correct description of the adenomyotic pathology. Current efforts to classify the disease contributed a lot in elucidated the potential characteristics that a classification system should be relied on. The need for a comprehensive, user friendly, and clear categorization of adenomyosis including the pattern, location, histological variants, and the myometrial zone seems to be an urgent need. With the uterus as a possible unifying link between adenomyosis and endometriosis, exploration of the uterus should not only be restricted to the hysteroscopic exploration of the uterine cavity but in a fusion with ultrasound. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/29040-25436 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/29040-25436 Already described in 1860 by Karl Freiherr von Rokitansky (1Rokitansky C. Über uterusdrüsen-neubildung in uterus- und ovarial-sarcomen.Zeitschr Gesellschaft der Aerzte Wien. 1860; 16: 577-581Google Scholar) in the German literature as “fibrous tumors containing gland like structures that resemble endometrial glands,” in 1920 by Cullen (2Cullen T.S. The distribution of adenomyomata containing uterine mucosa.Arch Surg. 1920; 1: 215-283Crossref Google Scholar) as “endometriosis with predominantly presence of fibromuscular tissue,” and in 1921 by Sampson (3Sampson J.A. Perforating hemorrhagic (chocolate) cysts of the ovary: their importance and especially their relation to pelvic adenomas of the endometrial type.Arch Surg. 1921; 3: 245-253Crossref Google Scholar) distinguishing three types of adenomyosis, adenomyosis received little attention in the later decades and remained for a long time the small appendix in books on endometriosis despite a high impact on women's health. As adenomyosis could only be diagnosed definitively on histological specimens obtained after hysterectomy, the estimated incidence in retrospective studies varied between 5%-70% (4Azziz R. Adenomyosis: current perspectives.Obstet Gynecol Clin North Am. 1989; 16: 221-235Abstract Full Text PDF PubMed Google Scholar) and differences in prevalence are due to the criteria used. A classical histological definition for adenomyosis is the invasion of the myometrium by endometrial glands and/or stroma, deeper than 2.5 mm from the endometrial –myometrial junction, accompanied by adjacent smooth muscle hyperplasia. It should be noted, however, that there are still different options in the definition of the disease ranging from the simple disruption of the endometrial –myometrial junction to a depth more than 8 mm or even relating the necessary depth of invasion to the myometrial thickness (5Habiba M, Benagiano G. The incidence and clinical significance of adenomyosis. In: Habiba M, Benagiano G, eds. Uterine adenomyosis. Switzerland: Springer Cham.Google Scholar). With the introduction and evolution of new imaging tools, adenomyosis moved from a histological diagnosis to a clinical entity. Ultrasound and magnetic resonance imaging (MRI) heralded a real turning point in the appreciation of adenomyosis as an important disorder of the female reproductive tract. The systematic use of these technics enables visualization of the myometrial architecture's distortions in a non-invasive way, distinguishing also the pathology of the outer and the inner myometrium or junctional zone (JZ). In contrast to the outer myometrium the JZ is hormonal dependent and is not only structurally but also functionally different from the outer myometrium. In women cycle dependent contractions are originated from the JZ in the late follicular phase in a cervical-fundal direction and in the late luteal phase in a fundal-cervical direction (6Wildt L. Kissler S. Licht P. Becker W. Sperm transport in the human female genital tract and its modulation by oxytocin as assessed by hysterosalpingoscintigraphy, hysterotonography, electrohysterography and Doppler sonography.Hum Reprod Update. 1998; 4: 655-666Crossref PubMed Scopus (113) Google Scholar). A dysregulation of these contractions has been described in patients with endometriosis and adenomyosis resulting in dysperistalsis and hyperperistalsis, constituting the main mechanism of uterine auto-traumatization (7Kissler S. Zangos S. Wiegratz I. Kohl J. Rody A. Gaetje R. et al.Utero-tubal sperm transport and its impairment in endometriosis and adenomyosis.Ann N Y Acad Sci. 2007; 1101: 38-48Crossref PubMed Scopus (67) Google Scholar). Despite the high prevalence of adenomyosis, the possibility of a pre-histologic identification and the severity of the symptoms interfering with women's health, the pathogenesis of adenomyosis is not well understood (8García-Solares J. Donnez J. Donnez O. Dolmans M. Pathogenesis of uterine adenomyosis: invagination or metaplasia?.Fertil Steril. 2018; 109: 371-379Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). This lack of knowledge contributes to the lack of consensus on the classification. Like endometriosis, adenomyosis may present itself in various disguises, ranging from simple JZ thickening to focal, cystic, or diffuse lesions. However JZ thickening or hyperplasia and focal lesions of the junctional zone have to be interpreted carefully as changes of the JZ can be due to the cyclic hormonal variations and to the thickening of the JZ by aging (9Kunz G. Herbertz M. Beil D. Huppert P. Leyendecker G. Adenomyosis as a disorder of the early and late human reproductive period.Reprod Biomed Online. 2007; 15: 681-685Abstract Full Text PDF PubMed Scopus (86) Google Scholar, 10Hauth E.A. Jaeger H.J. Libera H. Lange S. Forsting M. MR imaging of the uterus and cervix in healthy women: determination of normal values.Eur Radiol. 2007; 17: 734-742Crossref PubMed Scopus (51) Google Scholar). Focal lesions are well circumscribed and can present either as a muscular or cystic lesion. Borders of diffuse lesions are not well circumscribed and can involve partially or entirely the posterior and/or anterior uterine wall resulting in an increased uterine and asymmetric volume. The accuracy of the ultrasound in the diagnosis of adenomyosis is high with a mean sensitivity of 0.72 (95% confidence interval [CI] 0.65-0.79), specificity of 0.81 (95% CI 0.77-0.85), and area under the curve (AUC) of 0.85 (11Champaneria R. Abedin P. Daniels J. Balogun M. Khan K.S. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy.Acta Obstet Gynecol Scand. 2010; 89: 1374-1384Crossref PubMed Scopus (141) Google Scholar); however, its diagnostic performance is biased by the experience of the examiner. With a higher diagnostic accuracy having a sensitivity of 77% (95% CI 67–85%), specificity of 89% (11Champaneria R. Abedin P. Daniels J. Balogun M. Khan K.S. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy.Acta Obstet Gynecol Scand. 2010; 89: 1374-1384Crossref PubMed Scopus (141) Google Scholar), and AUC of 0.93, MRI, although more costly, has the advantage that it is less operator-dependent and diagnosis is based on objective image findings. MRI shows an excellent soft tissue differentiation with a clear identification of the junctional zone. It is hard to allocate one pathognomic symptom to the presence of adenomyosis. Symptoms associated with adenomyosis are pelvic pain (in the forms of dysmenorrhea, dyspareunia, and chronic pelvic pain), abnormal uterine bleeding, impaired reproductive potential, and feeling of swelling; however, approximately 30% patients with adenomyosis are asymptomatic (12Peric H. Fraser I.S. The symptomatology of adebomyosis.Best Pract Res Clin Obstet Gynaecol. 2006; 20: 547-555Crossref PubMed Scopus (92) Google Scholar). Furthermore, concomitant diseases with similar symptomatology are frequently present, masking the causal relationship between the disease and the symptoms; most frequent coexisting morbidities are endometriosis and fibroids. The incidence of adenomyosis as an isolated pathology is not clear, ranging from 38% to 64% (13Naftalin J. Hoo W. Pateman K. Mavrelos D. Foo X. Jurkovic D. Is adenomyosis associated with menorrhagia?.Hum Reprod. 2014; 29: 473-479Crossref PubMed Scopus (62) Google Scholar). Although a strict consensus on the association of adenomyosis and dysmenorrhea is debatable, the incidence of dysmenorrhea was reported between 50% and 93.4% (14Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI Study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 15Li X. Liu X. Guo S.W. Clinical profiles of 710 premenopausal women with adenomyosis who underwent hysterectomy.J Obstet Gynaecol Res. 2014; 40: 485-494Crossref PubMed Scopus (47) Google Scholar, 16Pinzauti S. Lazzeri L. Tosti C. Centini G. Orlandini C. Luisi S. et al.Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms.Ultrasound Obstet Gynecol. 2015; 46: 730-736Crossref PubMed Scopus (90) Google Scholar, 17Taran F.A. Wallwiener M. Kabashi D. Rothmund R. Rall K. Kraemer B. et al.Clinical characteristics indicating adenomyosis at the time of hysterectomy: a retrospective study in 291 patients.Arch Gynecol Obstet. 2012; 285: 1571-1576Crossref PubMed Scopus (28) Google Scholar). Women with leiomyomas and adenomyosis had an odds ratio of 3.4 (95% CI 1.8-6.4) to have more dysmenorrhea than women with only fibroids (17Taran F.A. Wallwiener M. Kabashi D. Rothmund R. Rall K. Kraemer B. et al.Clinical characteristics indicating adenomyosis at the time of hysterectomy: a retrospective study in 291 patients.Arch Gynecol Obstet. 2012; 285: 1571-1576Crossref PubMed Scopus (28) Google Scholar). A linear correlation between the extent of the adenomyosis and the severity of dysmenorrhea was described (16Pinzauti S. Lazzeri L. Tosti C. Centini G. Orlandini C. Luisi S. et al.Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms.Ultrasound Obstet Gynecol. 2015; 46: 730-736Crossref PubMed Scopus (90) Google Scholar, 18Kissler S. Zangos S. Kohl J. Wiegratz I. Rody A. Gätje R. et al.Duration of dysmenorrhoea and extent of adenomyosis visualised by magnetic resonance imaging.Eur J Obstet Gynecol Reprod Biol. 2008; 137: 204-209Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). The problem of dysmenorrhea and pelvic pain in women with adenomyosis is not well understood, but prostaglandins may play an important role (19Harel Z. Dysmenorrhea in adolescents and young adults: from pathophysiology to pharmacological treatments and management strategies.Expert Opin Pharmacother. 2008; 9: 2661-2672Crossref PubMed Scopus (61) Google Scholar). In contrast with deep endometriosis, the presence of nerve fibers as a possible explanation for pain were described (20Anaf V. Simon P. El Nakadi I. Fayt I. Buxant F. Simonart T. et al.Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules.Hum Reprod. 2000; 15: 1744-1750Crossref PubMed Scopus (260) Google Scholar), the presence of nerve fibers in uterine adenomyosis is still a matter of debate (21Quinn M. Uterine innervation in adenomyosis.J Obstet Gynaecol. 2007; 27: 287-291Crossref PubMed Scopus (43) Google Scholar, 22Zhang X. Lu B. Huang X. Xu H. Zhou C. Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids.Fertil Steril. 2010; 94: 730-737Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Post hysterectomy specimens showed absence of nerves in areas of adenomyosis at the endometrial-myometrial nerve plexus. Focal proliferation of small-diameter nerve fibers was observed at the margins of adenomyosis in some uteri (21Quinn M. Uterine innervation in adenomyosis.J Obstet Gynaecol. 2007; 27: 287-291Crossref PubMed Scopus (43) Google Scholar). Uterine hyperperistalsis and the increased expression levels of oxytocin receptor in patients with adenomyosis may contribute to the severity of the dysmenorrhea (14Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI Study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar). In the presence of co-existing morbidity like uterine fibroids and inclusion of multiparous women, the causal effect of adenomyosis is hard to prove. However a higher incidence of abnormal uterine bleeding in nulliparous women with diffuse adenomyosis suggested by ultrasound examination was described by Pinzauti et al. (16Pinzauti S. Lazzeri L. Tosti C. Centini G. Orlandini C. Luisi S. et al.Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms.Ultrasound Obstet Gynecol. 2015; 46: 730-736Crossref PubMed Scopus (90) Google Scholar). Naftalin et al. (13Naftalin J. Hoo W. Pateman K. Mavrelos D. Foo X. Jurkovic D. Is adenomyosis associated with menorrhagia?.Hum Reprod. 2014; 29: 473-479Crossref PubMed Scopus (62) Google Scholar) reported a significant 22% increase in menstrual loss for each additional feature of adenomyosis [OR 1.21 (95% CI: 1.04–1.40). McCausland (23McCausland A.M. Hysteroscopic myometrial biopsy: its use in diagnosing adenomyosis and its clinical application.Am J Obstet Gynecol. 1992; 166: 1619-1628Abstract Full Text PDF PubMed Scopus (111) Google Scholar) in an attempt to estimate the amount of blood loss quantified the clot size in four categories. He found a statistically significant correlation between the depth of adenomyosis and the severity of abnormal uterine bleeding (AUB). Although the genesis of abnormal uterine bleeding in cases of adenomyosis is difficult to prove, the PALM-COEIN classification (24Munro M.G. Critchley H.O. et al.FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in non-gravid women of reproductive age.Int J Gynaecol Obstet. 2011; 113: 3-13Crossref PubMed Scopus (504) Google Scholar) included adenomyosis as a cause of AUB in women of reproductive age. In hysterectomy specimens of patients with AUB, the prevalence of adenomyosis was 34.3%–49% (25Pervez S.N. Javed K. Adenomyosis among samples from hysterectomy due to abnormal uterine bleeding.J Ayub Med Coll Abbottabad. 2013; 25: 68-70PubMed Google Scholar, 26Mobarakeh M.D. Maghsudi A. Rashidi I. Adenomyosis among samples from hysterectomy due to abnormal uterine bleeding in Ahwaz, southern Iran.Adv Biomed Res. 2012; 1: 49Crossref PubMed Google Scholar). In the absence of concomitant pathology, adenomyosis caused AUB in 27%–65% of patients (Table 1). AUB can be due to an increased uterine volume, increased vascularization, improper uterine contractions and increased production of estrogen and prostaglandins. In a series of 111 specimens Levgur et al. (27Levgur M. Abadi M.A. Tucker A. Adenomyosis: symptoms, histology, and pregnancy terminations.Obstet Gynecol. 2000; 95: 688-691Crossref PubMed Scopus (169) Google Scholar) found that there was no correlation between the number of adenomyotic foci and the severity of AUB, but that heavy menstrual bleeding correlated with the depth of penetration. There is no clear consensus in the literature on the correlation between adenomyosis and heavy menstrual bleeding. Meticulous recording of concomitant pathology (fibroids, high body mass index, presence of endometrial polyps) and of the different features visualized at ultrasound will be important to identify the most plausible explanation responsible for AUB.Table 1Adenomyosis proven by histology as the only pathology in presence of abnormal uterine bleeding.StudyAUBOwolabi et al. 85Owolabi T.O. Strickler R.C. Adenomyosis: a neglected diagnosis.Obstet Gynecol. 1977; 50: 424-427PubMed Google Scholar (1977)65Bird et al. 68Bird C.C. McElin T.W. Manalo-Estrella P. The elusive adenomyosis of the uterus revisited.Am J Obstet Gynecol. 1972; 112: 583-593Abstract Full Text PDF PubMed Scopus (337) Google Scholar (1972)51.2Ozkan et al. 86Özkan Z.S. Kumbak B. Cilgin H. Simsek M. Turk B.A. Coexistence of adenomyosis in women operated for benign gynecological diseases.Gynecol Endocrinol. 2012; 28: 212-215Crossref PubMed Scopus (7) Google Scholar (2011)35Weiss et al. 87Weiss G. Maseelall P. Schott L.L. Brockwell S.E. Schocken M. Johnston J.M. Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).Fertil Steril. 2009; 91: 201-206Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar (2009)27Benson and Sneeden 88Benson R.C. Sneeden V.D. Adenomyosis: a reappraisal of symptomatology.Am J Obstet Gynecol. 1958; 76: 1044-1061Abstract Full Text PDF PubMed Scopus (122) Google Scholar (1958)38.4Note: Data presented as percent. AUB = abnormal uterine bleeding. Open table in a new tab Note: Data presented as percent. AUB = abnormal uterine bleeding. With the introduction of the concept of archimetra (28Noe M. Kunz G. Herbertz M. Mall G. Leyendecker G. The cyclic pattern of the immune-cytochemical expression of oestrogen and progesterone receptors in human myometrial and endometrial layers: characterization of the endometrial–subendometrial unit.Hum Reprod. 1999; 14: 190-197Crossref PubMed Scopus (156) Google Scholar) and the use of more sophisticated techniques of direct imaging adenomyosis became a different world. It became clear that the uterine myometrium was composed out of two structures: the outer myometrium and the inner myometrium also called sub endometrial layer or junctional zone. The latter is more akin to the endometrium and undergoes cycle dependent changes and is of müllerian origin while the outer myometrium is of non-müllerian, mesenchymal origin (28Noe M. Kunz G. Herbertz M. Mall G. Leyendecker G. The cyclic pattern of the immune-cytochemical expression of oestrogen and progesterone receptors in human myometrial and endometrial layers: characterization of the endometrial–subendometrial unit.Hum Reprod. 1999; 14: 190-197Crossref PubMed Scopus (156) Google Scholar). Dysperistalsis of cycle dependent contractions of the junctional zone in patients with endometriosis and adenomyosis results in a more pronounced retrograde menstruation and a disturbed uterine tubal sperm transport (14Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI Study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 29Kissler S. Siebzehnruebl E. Kohl J. Mueller A. Hamscho N. Gaetje R. et al.Uterine contractility and directed sperm transport assessed by hysterosalpingoscintigraphy (HSSG) and intrauterine pressure (IUP) measurement.Acta Obstet Gynecol Scand. 2004; 83: 369-374Crossref PubMed Scopus (36) Google Scholar). In presence of a dysregulation of the myometrial structure and an altered endometrial function (30Campo S. Campo V. Benagiano G. Infertility and adenomyosis.Obstet Gynecol Int. 2012; 2012: 786132Crossref PubMed Google Scholar) there is accumulating evidence of a negative impact of adenomyosis on fertility. Incidence of adenomyosis in patients with dysmenorrhea, menorrhagia, and infertility was reported to be as high as 50 % (31Brosens J.J. de Souza N.M. Barker FG Uterine junctional zone: function and disease.Lancet. 1995; 346: 558-560Abstract PubMed Scopus (159) Google Scholar). By postponing pregnancy till a later stage in reproductive life span, an increased frequency of adenomyosis can be expected in patients consulting for fertility problems. Adenomyosis was reported in 24.6%–70% of patients with endometriosis depending on the definition of adenomyosis and on the severity of the endometriotic disease (14Leyendecker G. Bilgicyildirim A. Inacker M. Stalf T. Huppert P. Mall G. et al.Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI Study.Arch Gynecol Obstet. 2015; 291: 917-932Crossref PubMed Scopus (137) Google Scholar, 32Kunz G. Beil D. Huppert P. Leyendecker G. Structural abnormalities of the uterine wall in women with endometriosis and infertility visualized by vaginal sonography and magnetic resonance imaging.Hum Reprod. 2000; 15: 76-82Crossref PubMed Scopus (151) Google Scholar, 33Larsen S.B. Lundorf E. Forman A. Dueholm M. Adenomyosis and junctional zone changes in patients with endometriosis.Eur J Obstet Gynecol Reprod Biol. 2011; 157: 206-211Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). In patients with deep endometriosis the prevalence of adenomyosis is 48.7%–66.3% (34Lazzeri L. Di Giovanni A. Exacoustos C. Tosti C. Pinzauti S. Malzoni M. et al.Preoperative and postoperative clinical and transvaginal ultrasound findings of adenomyosis in patients with deep infiltrating endometriosis.Reprod Sci. 2014; 21: 1027-1033Crossref PubMed Scopus (78) Google Scholar, 35Chapron C. Tosti C. Marcellin L. Bourdon M. Lafay-Pillet M.C. Millischer A.E. et al.Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes.Hum Reprod. 2017; 32: 1393-1401Crossref PubMed Scopus (133) Google Scholar). Necropsy in baboons with long life infertility showed the presence of adenomyosis in all of them with the presence of endometriosis in 43% (36Barrier B.F. Malinowski M.J. Dick Jr., E.J. Hubbard G.B. Bates G.W. Adenomyosis in the baboon is associated with primary infertility.Fertil Steril. 2004; 82: 1091-1094Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Lower pregnancy rates were reported after colorectal surgery for endometriosis in the presence of adenomyosis (36Barrier B.F. Malinowski M.J. Dick Jr., E.J. Hubbard G.B. Bates G.W. Adenomyosis in the baboon is associated with primary infertility.Fertil Steril. 2004; 82: 1091-1094Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 37Ballester M. d'Argent E.M. Morcel K. Belaisch-Allart J. Nisolle M. Daraï E. Cumulative pregnancy rate after ICSI-IVF in patients with colorectal endometriosis: results of a multicentre study.Hum Reprod. 2012; 27: 1043-1049Crossref PubMed Scopus (90) Google Scholar, 38Daraï E. Marpeau O. Thomassin I. Dubernard G. Barranger E. Bazot M. Fertility after laparoscopic colorectal resection for endometriosis: preliminary results.Fertil Steril. 2005; 84: 945-950Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). As adenomyosis can be present in different sizes, localizations, and forms, a clear description of these lesions when reporting on results is mandatory. It is still unclear if lesions located in the inner myometrium will have the same impact on implantation and fertility as the lesions in the outer myometrium. Can junctional zone hyperplasia be considered as pathology and if so which cutoff level of JZ thickness is relevant? In addition to this heterogeneity in phenotypes of adenomyosis and the lack of a good description of the lesions, is the use of different ovarian stimulation protocols, making the reported pregnancy rates after in vitro fertilization highly controversial. Reported results and understanding of adenomyosis is greatly hampered by a lack of agreed-upon terminology or consensus on the classification of the lesions (39Gordts S. Brosens J.J. Fusi L. Benagiano G. Brosens I. Uterine adenomyosis: a need for uniform terminology and consensus classification.Reprod Biomed Online. 2008; 17: 244-248Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 40Bazot M. Darai E. Role of transvaginal sonography and magnetic resonance imaging in the diagnosis of uterine adenomyosis.Fertil Steril. 2018; 109: 389-397Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). In two recent meta-analyses (41Vercellini P. Consonni D. Dridi D. Bracco B. Frattaruolo M.P. Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis.Hum Reprod. 2014; 29: 964-977Crossref PubMed Scopus (245) Google Scholar, 42Younes G. Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis.Fertil Steril. 2017; 108: 483-490Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) adenomyosis was associated with a 30% decrease in the likelihood of pregnancy. Use of a gonadotropin-releasing hormone agonist long protocol for ovarian stimulation seems beneficial in patients undergoing assisted reproductive technology (41Vercellini P. Consonni D. Dridi D. Bracco B. Frattaruolo M.P. Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis.Hum Reprod. 2014; 29: 964-977Crossref PubMed Scopus (245) Google Scholar). By measuring the junctional zone thickness absence of pregnancy after IVF was reported in 95.8% of the patients when the average junctional zone thickness is > 7 mm and the maximal junctional zone thickness > 10 mm (43Maubon A. Faury A. Kapella M. Pouquet M. Piver P. Uterine junctional zone at magnetic resonance imaging: a predictor of in vitro fertilization implantation failure.J Obstet Gynaecol Res. 2010; 36: 611-618Crossref PubMed Scopus (93) Google Scholar). However, it was proposed that JZ thickening has to be considered as a disruption of the endometrial/sub-endometrial myometrium unit different from adenomyosis and, thus, those two entities are different (44Tocci A. Greco E. Ubaldi F.M. Adenomyosis and ‘endometrial-subendometrial myometrium unit disruption disease’ are two different entities.Reprod Biomed Online. 2008; 17: 281-291Abstract Full Text PDF PubMed Google Scholar). In patients with adenomyosis referred for oocyte donation, a lower implantation rate was not observed and there was a normal expression of the genes linked with implantation, however a higher miscarriage rate was reported (45Martínez-Conejero J.A. Morgan M. Montesinos M. Fortuño S. Meseguer M. Simón C. et al.Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation.Fertil Steril. 2011; 96: 943-950Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). A two-fold increase in miscarriage rate was also reported in the meta-analysis of Vercellini et al. (41Vercellini P. Consonni D. Dridi D. Bracco B. Frattaruolo M.P. Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis.Hum Reprod. 2014; 29: 964-977Crossref PubMed Scopus (245) Google Scholar). Recently a higher incidence of miscarriages was reported in patients with endometriosis (46Pallacks C. Hirchenhain J. Krüssel J.S. Fehm T.N. Fehr D. Endometriosis doubles odds for miscarriage in patients undergoing IVF or ICSI.Eur J Obstet Gynecol Reprod Biol. 2017; 213: