{"paper_id":"73f26b10-eb09-4100-b903-dcf3895be4bc","body_text":"Adenomyosis associated with infertility is still an enigma for the treating\nclinician. Women with adenomyosis have lower implantation rate per embryo transfer,\nlower clinical pregnancy rate and higher spontaneous abortion rate as compared to\nwomen without adenomyosis.\nAlthough the exact mechanism behind the relationship between adenomyosis and\ninfertility is still unclear, a number of factors has been proposed and focus on\nfour putative pathways: (i) Intrauterine abnormalities and increased uterine\nperistalsis causing abnormal utero-tubal sperm and embryo transport. Intrauterine\nanatomical distortion caused by uterine hyper peristalsis and inflammation-induced\nadnexal adhesion may block the tubal ostia and potentially impair sperm migration\nand embryo transport ( Harada  et al .,\n2016 ;  Brosens  et al .,\n2004 ). (ii) Abnormal endometrial steroid metabolism, increased\ninflammatory response, and increased intrauterine oxidative stress environment\nleading to altered endometrial function and receptivity ( Brosens  et al ., 2004 ). The increased density of\nmacrophages increases inflammatory response of the endometrium and release of\nreactive oxygen species that are thought to be embryotoxic. (iii) Impairment of\nimplantation may result from inflammation, a lack of adequate expression of adhesion\nmolecules (integrins), reduced expression of implantation markers, such as leukemia\ninhibitory factor (LIF), and altered function of the gene for embryonic development\n(HOXA10) ( Emge, 1962 ) (iv) Occurrence of\nchronic endometritis (CE) resulting from intrauterine microbial infection may be\nassociated with negative fertility outcome in women with adenomyosis.\nThe prevalence of adenomyosis in a population of infertile women ranges between 7%\nand 27% ( Dueholm & Aagaard, 2018 ). If\nwomen with adenomyosis undergo an in vitro fertilization treatment, there will be a\nsignificant reduction in clinical pregnancy and delivery rates as compared to women\nwithout adenomyosis (a clinical pregnancy rate of 41%  vs . 50% and\nof 26.8%  vs . 37.1%) ( Mavrelos\n et al ., 2017 ) Miscarriage occurs in 32% women with\nadenomyosis and 14% in those without adenomyosis ( Vercellini  et al ., 2014 ). Even with maximum possible\ncytoreduction spontaneous pregnancy rate in women with adenomyosis is 60%. In cases\nwhere only partial excision is done, these results decreased to 47%. It should be\nknown that none of these data are from randomized trials, but mostly from small and\nretrospective series ( Mavrelos  et\nal ., 2017 ).\nAdenomyosis associated with subfertility is a situation of a dilemma for the treating\nclinician as the treatment is highly controversial and there remains an overall lack\nof consensus regarding the value of conservative surgery with or without medical\nmanagement to improve reproductive outcomes  Leyendecker  et al . (2015) . Also, there is no\nstandardization on when and whom to operate and surgical techniques to be used.\nExisting literature demonstrates increased miscarriage rates and poor pregnancy\noutcomes in such women depending on the extent of abnormal uterine myometrium with\ndifferent cell density and immunohistochemistry as compared to normal uterine\nmyometrium.\nThere have been many attempts to classify adenomyosis based on Histopathology,\nUltrasound and MRI features and MUSA (Morphological Uterine sonographic assessment)\nbeing the most accepted one. But none of the classifications have been able to\nprognosticate the treatment outcomes in women with adenomyosis with infertility.\nThis necessitates the need for a more simple and stratified approach to adenomyosis\nclassification for universal and standardized management.\nHence, we proposed this classification based on mapping of the size of adenomyoma,\nits location, distance from endometrial cavity and any associated endometriosis by\nstudying 100 women with adenomyosis undergoing IVF.\n\nInfertile women presenting to IVF OPD underwent transvaginal ultrasound as a part of\nroutine infertility workup. The sonography was done by a single experienced\nradiologist using a transvaginal probe of 8 MHz and women with ultrasound features\nof adenomyosis as per MUSA adenomyosis criteria were taken up in the study group.\nMUSA adenomyosis ultrasound features include: Asymmetrical thickening, fan shape\nshadowing, cyst, hyperechoic island, echogenic sub endometrial lines and buds, trans\nlesion vascularity, irregular junctional zone, and interrupted junctional zone.\nAdenomyosis was further classified based on the size and location of adenomyoma and\nits relation to endometrial cavity, into 4 categories ( Figure 1 ):\nFigure 1 Proposed adenomyosis classification.\nProposed adenomyosis classification.\nGrade 1:  Adenomyoma less then 4cms in size. It is further subclassified\ninto A and B\nGrade 1A - away from the cavity\nGrade 1B - touching or compressing the endometrial cavity.\nGrade 2:  Adenomyoma greater than 4cms in size\nGrade 2A - Away from the cavity\nGrade 2B - Touching/compressing the cavity.\nGrade 3:  Diffuse adenomyosis.\nGrade 4:  Localized/diffuse disease with associated pelvic\nendometriosis.\n4 cm criteria: As most criteria’s for fibroid removal have 4 cm as cut off, hence we\nare considering the same size for adenomyosis in our study.\nThe best way to study the impact of adenomyosis on implantation is to study the\nadenomyosis patients requiring IVF. The question that “Does the presence of\nadenomyosis have deleterious effect on fertility and if so, does Pre-embryo transfer\ntherapy will improve the results?” is still an enigma.\n\nBased on the proposed classification, a prospective cohort study was conducted in\ndepartment of IVF and Endoscopy over a period of 2 years from July 20 - July 22.\nStudy population included women with uterine adenomyosis undergoing IVF.\nWomen with adenomyosis undergoing IVF.\nWomen with evidence of uterine fibroid or any other structural anomaly of\nuterus.\nWomen with male factor infertility\n3. Women with Ovulatory dysfunction.\nA sample size of convenience of 100 women was taken. A survey sheet was prepared\nto obtain all the necessary information. All the information obtained was\nrecorded in the predetermined format.\nWe took a sample size of convenience of 100 women with adenomyosis who were\nundergoing IVF with long agonist protocol and frozen embryo transfer.\n1. Women with Grade 1A and 1B adenomyosis were treated with medical management in\nthe form of 6 months of GnRH injection followed by a frozen embryo transfer in\nHRT cycle.\n2. Patients with Grade 2A were offered medical management with GnRH agonist\ninjection (1-2 doses) and Grade 2B or those who were refractory to medical\nmanagement with GnRH were taken up for surgery (adenomyomectomy). Refractory to\nmedical management was defined as decrease in size of adenomyosis by less than\n20% of original volume.\n3.Women with diffuse adenomyosis in Grade 3 who failed medical management were\noffered surrogacy.\n4.Women in Grade 4 with adenomyosis with endometriosis with hydrosalpinx were\noffered surgery in the form of endometrioma excision with adhesiolysis and\nhydrosalpinx excision. For adenomyosis, surgery was offered for local lesions\nfollowed by GnRH and in diffuse cases, 1-2 doses of GnRH 11.25 mg were\ngiven.\nA simple grid was prepared to collate the data in the survey sheet and proportion\nof responses for each question was calculated.\nThe study was approved by institutional ethics committee.\n\nA total of 100 women with adenomyosis who underwent IVF were studied. The mean age of\nparticipants was 32 years. Most of the subjects in the study group belonged to upper\nand upper middle socioeconomic status by modified Kuppuswami scale. 56% women\nbelonged to grade 1, 24% to grade 2, 8% to grade 3 and 12 % to Grade 4 Adenomyosis\naccording to our classification ( Table\n1 ).\nManagement and pregnancy outcomes.\nDecrease in volume of adenomyoma sufficient enough to keep the compression away from\ncavity was the criteria to decide results of medical management before proceeding\nwith FET.\n1. All the women with Grade 1 adenomyosis (n=56) were given medical management in the\nform of injection GnRH 11.25 mg for 3 months and then followed by Frozen embryo\ntransfer in HRT cycle. 71.4% (n=40) had a positive pregnancy result.\n2. All the women with Grade 2 adenomyosis (n=24) were initially given trial of\nmedical management with 2 doses of 11.25 mg GnRH. Out of 24 women, 16 women (66.6%)\nresponded and showed a regression in size of adenomyosis sufficient enough to be\ntaken for transfer. A frozen embryo transfer was planned for such women with medical\nmanagement and 12 out of 16 women (75%) showed a positive pregnancy test. Rest of\nthe 8 women (33.3%) were taken up for adenomyomectomy in view of failed medical\nmanagement. Post-surgery GnRH 11.25 mg was also given. 4 out of 8 women (50%) showed\na positive pregnancy test.\n3. 8 women with diffuse adenomyosis (Grade 3) were initially offered medical\nmanagement with 11.25 GnRH but they did not respond and had to resort to\nsurrogacy.\n4. The remaining 12 patients had Grade 4 adenomyosis with endometriosis and/ or\nHydrosalpinx. Out of 12, 5 were treated with 2 doses of GnRH 11.25mg. 4 patients had\nhydrosalpinx and have to undergo lap hydrosalpinx excision before FET in subsequent\ncycle. Rest 3 had adenomyoma compressing the cavity with failed medical management\nand underwent adenomyomectomy with adhesiolysis. Total 8 out of 12 (66.6%) had a\npositive pregnancy test after frozen embryo transfer in this group.\n\nIn literature, there is no consensus over size of adenomyoma which should be\nmedically managed. but based on our study and supporting medical literature, we\npropose that in a non-cavity distorting adenomyoma less than 4 cm, medical\nmanagement can improve the pregnancy rates.\nIn our study, 56% of women were given GnRH 11.25 mg for suppression of HPO axis for 3\nmonths and a frozen embryo transfer was done. It leads to decrease in size of\nadenomyosis with improved receptivity and implantation. The pregnancy rate in grade1\nwas 71.4%. It is in concordance with other studies.  Lan  et al . (2021)  showed a pregnancy rate of 43% with\nmedical management of adenomyosis but in the study, there was no cut off to\ncategorize which cases are to be medically managed. Similarly,  Park  et al . (2016)  reported a pregnancy rate\nof 39.5% in this group.\nIn adenomyoma >4cm, management depends on the location of adenomyoma and its\ndistance from the endometrial cavity. When in contact with the cavity, it interferes\nwith adhesion and implantation of embryos and impairs the secretion of various\nimplantation factors. The authors propose that if adenomyoma >4cm but away from\ncavity, a trial of medical management should be given but in refractory cases or\nwhen the adenomyoma is touching the cavity, surgery should be considered. No one\nparticular method of treatment is wholly satisfactory to achieve pregnancy in the\nnulliparous infertile patient with extensive adenomyosis, and patients should be\nmade to understand this before any treatment is commenced.\nIn our study, the pregnancy rate was 66.6% in patients with adenomyosis >4cm and\nwere given 3-6 months of GnRh suppression therapy followed by frozen embryo\ntransfer.\nThe pregnancy rate in group who were given medical treatment but did not respond\nsatisfactorily and were treated with surgery (adenomyomectomy), the pregnancy rate\nwas 33.3%.\nAl Jama  et al . ( 2011 )\ndemonstrated that combined surgical and hormonal treatment had significant benefits\nwith pregnancy rate of 44%.  Tsui  et\nal . (2015)  showed a pregnancy rate of 46% in women treated\nwith adenomyomectomy.  Dueholm & Aagaard\n(2018)  showed a pregnancy rate of 47% after surgery in women with\nadenomyosis.\nUterus-sparing resection of adenomyosis is still an investigational approach\nespecially in patients with extensive adenomyosis who are actively pursuing\npregnancy. Adenomyomectomy is done for focal adenomyosis wherein, adenomyoma is\nseparated and excised from the normal myometrial tissue. The technique is similar to\nmyomectomy, although, the plane between normal myometrium and adenomyoma is well\ndefined and the preferred route is laparoscopic adenomyomectomy. The defect is\nclosed with meticulous suturing without leaving any dead space. The best method of\nsurgery is yet to be proven. It was found that, the best minimum wall thickness for\nexcision of the uterus ranges from 9 to 15 mm ( Otsubo\n et al ., 2016 ) for conception and preventing uterine\nrupture during pregnancy, while women with a uterine wall thickness of ≤7 mm\nmay have an elevated risk of subsequent uterine rupture. Thus, wall thickness may be\na useful indicator for primary obstetrical management.\nIt includes diffuse disease which requires long term medical hormonal therapy.\nHowever due to extensive anatomical and molecular damage, patients may have to turn\nto surrogacy as an option. Uterine sparing surgeries should be avoided as much as\npossible in such cases because the associated risks outweigh the benefits.  Otsubo  et al . (2016)  presented\nresults of fertility-saving surgical excisions of diffuse adenomyotic foci and\nsuggested that preservation of a 9 to 15 mm thickness of the uterine wall after\nexcision with classical surgical methods is safe for future pregnancies. But this\nmight not be possible in cases of diffuse adenomyosis. Even when performed by expert\nsurgeons, the rate of uterine rupture in a future pregnancy appears to be 4%. This\nrate exceeds the uterine rupture rate after myomectomy or classical cesarean birth\n(2%) ( Otsubo  et al . 2016 ).\nApart from this, there are also increased chances of failed implantation, early\nabortions and morbidly adherent placenta which can be an obstetrician’s\nnightmare.\nThe treatment of such patients is usually surgical. Clipping or excision of\nhydrosalpinx is an important component in such patients. We performed adhesiolysis\nwith endometrioma excision with bilateral hydrosalpinx excision in these patients\nand. In our study, the pregnancy rate in this group after surgery was 66.6%.  Shi  et al.  (2021)  had done a\nstudy on similar group of patients and shown a pregnancy rate of 51.8% through IVF\nafter laparoscopic surgery in such patients.\nWomen with grade I and II A are the candidates who will be significantly benefited\nfrom medical management. Unnecessary surgery is thus avoided in such patients\nreducing cost. Surgery was offered to refractory (to medical management) cases with\ngrade II B and grade IV cases as adenomyoma in such cases was compressing uterine\ncavity or was associated with dense pelvic adhesion.\nThe biggest limitation of the current study is the lesser sample size. Hence, further\nresearch must be done including larger study population. Also, the primary outcome\nstudied here is the clinical pregnancy rate. The fact that adenomyosis itself is\nassociated with significantly increased risk of abortion cannot be overlooked. This\nemphasizes need for follow up of these women in order to assess the correlation\nbetween the proposed management protocol and the live birth rate.\n\nOur classification is simple and allows cost effective management based on location\nand extent of disease with the help of ultrasonography. It also helped us to\nsimplify the treatment protocol in patients with adenomyosis and infertility in the\nunit to achieve desired results.","source_license":"public-domain-us","license_restricted":false}