Until recently, adenomyosis has been associated with multiparity, not impaired fertility. Currently, adenomyosis is diagnosed with increasing frequency in infertile patients since women delay their ...first pregnancy until their late 30s or early 40s. Although an association between adenomyosis and infertility has not been fully established, based on the available information, recent studies suggested that adenomyosis has a negative impact on female fertility. Several uncontrolled studies with limited data also suggested that treatment of adenomyosis may improve fertility. This article discusses (i) the hypothesis and epidemiology of adenomyosis, (ii) diagnostic techniques, (iii) clinical evidence of correlation between adenomyosis and infertility, (iv) proposed mechanism of infertility in women with adenomyosis, (v) different treatment strategies and reproductive outcomes, and (vi) assisted reproductive technology outcome in women with adenomyosis.
To review systematically the literature on uterus-sparing surgical treatment options for adenomyosis.
Systematic literature review.
Tertiary academic center.
Women with histologically proven ...adenomyosis treated with uterus-sparing surgical techniques.
Conservative uterine-sparing surgery for adenomyosis classified as (1) complete excision of adenomyosis, (2) cytoreductive surgery or incomplete removal of the lesion, or (3) nonexcisional techniques, with studies selected if women with adenomyosis were treated surgically without performing hysterectomy.
The cure rate after interventional strategies, the rate of symptom (dysmenorrhea and menorrhagia) control, and pregnancy rate in each group of intervention.
A quality assessment tool was used to assess the scientific value of each study. In total, 64 studies dealing with 1,049 patients were identified. After complete excision, the dysmenorrhea reduction, menorrhagia control, and pregnancy rate were 82.0%, 68.8%, and 60.5%, respectively. After partial excision, the dysmenorrhea reduction, menorrhagia control, and pregnancy rate were 81.8%, 50.0%, and 46.9%, respectively.
Uterine-sparing operative treatment of adenomyosis and its variants appear to be feasible and efficacious. Well-designed, comparative studies are urgently needed to answer the multiple questions arising from this intriguing intervention.
BACKGROUND Adenomyosis and endometriosis were initially described as 'adenomyoma'. When the retrograde menstruation theory became widely accepted to explain the pathogenesis of endometriosis, since ...it does not explain adenomyosis, the two conditions came to be seen as distinct entities. However, emerging evidence suggests that both diseases may be linked to changes in the inner portion of the myometrium. In addition, similar anomalies were found in the eutopic endometrium of the two conditions and the debate has re-opened. A common origin for both adenomyosis and endometriosis would have relevance not only for understanding uterine function and pathophysiology, but also for clinical management and treatment. METHODS The Scopus and Medline databases were searched for all original articles published in English up to the end of 2012. Search terms included 'adenomyosis'; 'endometriosis'; 'endometrium'; 'eutopic endometrium'; 'inner myometrium'; 'junctional zone'. Special attention was paid to articles comparing features of eutopic endometrium in the two conditions. RESULTS A number of similarities exist between adenomyosis and endometriosis and, by using magnetic resonance and laparoscopy, it was found that, at least in some subgroups, the two conditions often coexist. In both situations the inner myometrium (or junctional zone) is altered, although alterations are much more marked in adenomyosis where a thickness >12 mm is today considered sufficient for diagnosis. Research has shown differences between the eutopic endometrium of women with both diseases when compared with controls. There is an immune dysfunction and there are alterations of adhesion molecules, cell proliferation and apoptosis. An increase in cytokines and inflammatory mediators has also been observed. Finally, the presence of oxidative stress and anomalies in free-radical metabolism may alter uterine receptivity. When the two conditions were compared, dissimilarities were also observed in the extent of apoptosis inhibition and in the expression of some inflammatory mediators. It is not clear if observed differences are primarily related to presenting symptoms. Finally, both conditions are steroid dependent and research suggests a role for epigenetic mechanisms. The analysis indicates that much of the published research may have been influenced by the method of diagnosis and/or has not been controlled for the presenting symptoms, the concomitant presence of both diseases or full consideration of fluctuations within cycle phase. CONCLUSIONS It is difficult to draw firm conclusions from existing evidence since major diagnostic limitations still exist and there is a systematic bias in clinical presentation. In addition, scanty information is available on the natural history of endometriosis and no studies exist on the natural history of adenomyosis. Notwithstanding these limitations, a number of similarities, but also some differences have been found between the eutopic endometrium in the two diseases. These findings need to be taken with considerable caution as the few instances where the research was repeated yielded conflicting results.
The current study was designed to evaluate the relationship between adenomyosis and its subtypes with endometriotic lesions (ovarian endometrioma (OMAs) and posterior deep infiltrative endometriosis ...(DIE)), to examine the probability of existence of a common cause of these mysterious diseases, and to evaluate the accuracy, sensitivity, and specificity of both transvaginal ultrasonography (TVS) and MRI in diagnosis of adenomyotic uterus. In this retrospective cross-sectional study, we selected 154 women with coexistence of endometriosis and adenomyosis according to their imaging, intraoperative, or pathological findings who were nominated for laparoscopic surgery. Eighty-six patients with just DIE resection without LH (laparoscopic hysterectomy) (group 1), and 68 patients with LH + DIE resection (group 2). The accuracy, sensitivity, and specificity of ultrasonographic and MRI findings for diagnosing adenomyosis were 72.1%, 77.6%, 40.0% and 49.2%, 41.5%, 90.0% respectively. So, TVS is a more sensitive diagnostic tool for diagnosing adenomyosis. However, MRI was more specific than TVS in the diagnosis of diffuse adenomyosis especially with simultaneous presence of uterine leiomyoma. Regarding the association of different types of adenomyosis (focal and diffuse) with different endometriosis lesions (OMA and posterior compartment DIE), we just found diffuse type of adenomyosis more frequent in the absence of rectal and rectovaginal septum (RVS) DIE (p ≤ 0.05). In addition to the questionable different nature of rectal and RVS DIE lesion, there is no relationship between adenomyosis subtypes and endometriotic lesions.
To compare the efficacy of a selective progesterone receptor modulator, ulipristal acetate, and a gonadotropin-releasing hormone antagonist, linzagolix, in a case of severe uterine adenomyosis.
Case ...report.
Private clinic and infertility research unit.
One patient born in 1981 who presented because of heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis confirmed by magnetic resonance imaging (MRI).
The patient received a first treatment of 5 mg UPA daily for one course of 3 months. This therapy was discontinued because MRI revealed a worsened aspect. One year later, a once-daily dose of 200 mg linzagolix administered orally was initiated for 3 months, followed by another 3-month course of 100 mg once daily.
Clinical symptoms and MRI aspect.
During treatment with UPA, the symptoms (pelvic pain, dysmenorrhea, bulk symptoms) worsened and MRI revealed aggravation of the adenomyotic lesions. During the 12-week course of once-daily 200 mg linzagolix, the patient remained in amenorrhea and noted a very significant improvement in symptoms. On MRI, the uterine volume had fallen from 875 cm3 to 290 cm3, and the adenomyotic lesions had significantly regressed. During the 100-mg linzagolix course (weeks 13–24), the patient reported continued alleviation of her symptoms.
To our knowledge, this is the first reported use of linzagolix, a new oral gonadotropin-releasing hormone antagonist that significantly reduced lesion size and improved quality of life in a patient with severe adenomyosis, who was previously nonresponsive to treatment with a selective progesterone receptor modulator, ulipristal acetate.
Antagonista de hormona liberadora de gonadotropina (linzagolix): una nueva terapia para adenomiosis uterina.
Comparar la eficacia de un modulador selectivo de receptor de progesterona, acetato de ulipristal (UPA), y antagonista de hormona liberadora de gonadotropina, linzagolix, en casos severos de adenomiosis uterina.
Reporte de caso
Clínica privada y unidad de investigación de infertilidad.
Una paciente nacida en 1981 quien presentó sangrado menstrual severo, dolor pélvico y dismenorrea debido a adenomiosis difusa y severa confirmada por imagen de resonancia magnética (MRI).
La paciente recibió un primer tratamiento de 5mg de UPA diario por un curso de 3 meses. Esta terapia fue descontinuada porque la MRI reveló un aspecto empeorado. Un año después, una dosis diaria de 200 mg de linzagolix fue administrada vía oral por tres meses, seguido de otro curso de 3 meses de 100 mg diarios.
Síntomas clínicos y aspecto de MRI.
Durante el tratamiento con UPA, los síntomas (dolor pélvico, dismenorrea, inflamación) empeoraron y la MRI reveló aumento de severidad de las lesiones de adenomiosis. Durante el curso de 12 semanas de linzagolix 200 mg, la paciente permaneció en amenorrea con una notable mejoría de los síntomas. En la MRI, el volumen uterino disminuyó de 875 cm3 a 290 cm3, y las lesiones de adenomiosis presentaron una regresión importante. Durante el curso de linzagolix 100 mg (semanas 13 -24), la paciente reportó alivio continuado de sus síntomas.
Según nuestro conocimiento, este es el primer uso reportando de linzagolix, un nuevo antagonista oral de hormona liberadora de gonadotropina que significativamente reduce el tamaño de las lesiones y mejora la calidad de vida en una paciente con adenomiosis severa, quien previamente fue tratada sin respuesta con un modulador selectivo de los receptores de progesterona, acetato de ulipristal.
Abstract
BACKGROUND
Adenomyosis is a benign gynecological disorder associated with subfertility, pelvic pain and abnormal uterine bleeding that have significant consequences for the health and ...quality of life of women. Histologically, it is defined as the presence of ectopic endometrial islets within the myometrium. Its pathogenesis has not yet been elucidated and several pieces of the puzzle are still missing. One process involved in the development of adenomyosis is the increased capacity of some endometrial cells to infiltrate the myometrium. Moreover, the local and systemic immune systems are associated with the onset of the disease and with maintaining it. Numerous observations have highlighted the activation of immune cells and the release of immune soluble factors in adenomyosis. The contribution of immunity occurs in conjunction with hormonal aberrations and activation of the epithelial to mesenchymal transition (EMT) pathway, which promotes migration of endometrial cells. Here, we review current knowledge on the immunological changes in adenomyosis, with the aim of further elucidation of the pathogenesis of this disease.
OBJECTIVE AND RATIONALE
The objective was to systematically review the literature regarding the role of the immune system in development of adenomyosis in the inner and the outer myometrium, in humans.
SEARCH METHODS
A systematic review of published human studies was performed in MEDLINE, EMBASE and Cochrane Library databases from 1970 to February 2019 using the combination of Medical Subject Headings (MeSH): Adenomyosis AND (‘Immune System’ OR ‘Gonadal Steroid Hormones’), and free-text terms for the following search terms (and their variants): Adenomyosis AND (immunity OR immune OR macrophage OR ‘natural killer cell’ OR lymphocyte* OR leucocyte* OR HLA OR inflammation OR ‘sex steroid’ OR ‘epithelial to mesenchymal transition’ OR ‘EMT’). Studies in which no comparison was made with control patients, without adenomyosis (systemic sample and/or eutopic endometrium), were excluded.
OUTCOMES
A total of 42 articles were included in our systematic review. Changes in innate and adaptive immune cell numbers were described in the eutopic and/or ectopic endometrium of women with adenomyosis compared to disease-free counterparts. They mostly described an increase in lymphocyte and macrophage cell populations in adenomyosis eutopic endometrium compared to controls. These observations underscore the immune contributions to the disease pathogenesis. Thirty-one cytokines and other markers involved in immune pathways were studied in the included articles. Pro-inflammatory cytokines (interleukin (IL) 6, IL1β, interferon (IFN) α, tumor necrosis factor α, IFNγ) as well as anti-inflammatory or regulatory mediators (IL10, transforming growth factor β…) were found to be elevated in the eutopic endometrium and/or in the ectopic endometrium of the myometrium in women with adenomyosis compared to controls. Moreover, in women affected by adenomyosis, immunity was reported to be directly or indirectly linked to sex steroid hormone aberrations (notably changes in progesterone receptor in eutopic and ectopic endometrium) in three studies and to EMT in four studies.
WIDER IMPLICATIONS
The available literature clearly depicts immunological changes that are associated with adenomyosis. Both systemic and local immune changes have been described in women affected by adenomyosis, with the coexistence of changes in inflammatory as well as anti-inflammatory signals. It is likely that these immune changes, through an EMT mechanism, stimulate the migration of endometrial cells into the myometrium that, together with an endocrine imbalance, promote this inflammatory process. In light of the considerable impact of adenomyosis on women’s health, a better understanding of the role played by the immune system in adenomyosis is likely to yield new research opportunities to better understand its pathogenesis.
The aim of the present review, conducted according to PRISMA statement recommendations, was to evaluate the contribution of transvaginal sonography (TVS) and magnetic resonance imaging (MRI) to ...diagnose adenomyosis. Although there is a lack of consensus on adenomyosis classification, three subtypes are described, internal, external adenomyosis, and adenomyomas. Using TVS, whatever the subtype, pooled sensitivities, pooled specificities, and pooled positive likelihood ratios are 0.72-0.82, 0.85-0.81, and 4.67-3.7, respectively, but with a high heterogeneity between the studies. MRI has a pooled sensitivity of 0.77, specificity of 0.89, positive likelihood ratio of 6.5, and negative likelihood ratio of 0.2 for all subtypes. Our results suggest that MRI is more useful than TVS in the diagnosis of adenomyosis. Further studies are required to determine the performance of direct signs (cystic component) and indirect signs (characteristics of junctional zone) to avoid misdiagnosis of adenomyosis.
Objective
To compare the recurrence rate and risk factors between conservative surgery followed by medical treatments and conservative surgery‐only in patients with focal adenomyosis.
Methods
This ...retrospective study was conducted in a single teaching hospital from May 2011 to October 2016. All eligible patients were identified into three groups: surgery‐only group, surgery combined with gonadotropin‐releasing hormone agonist (GnRHa), and a levonorgestrel‐releasing intrauterine system (LNG‐IUS) group. The recurrence rate and risk factors were compared among groups using Kaplan–Meier and Cox proportional hazards analyses. Receiver operating characteristic (ROC) curve analysis was applied to determine a cut‐off value for identifying recurrence‐related risk factors.
Results
A total of 249 postoperative patients with adenomyosis were included in the final analysis with a mean of 41 months of follow up. The recurrence rate at the long‐term follow up was significantly lower in intervention groups than in the surgery‐only group (P = 0.011). The Cox proportional hazards and ROC analyses showed that a menstrual cycle longer than 26 days (P = 0.026), diameter of lesions <6 cm (P = 0.030), and combination treatment using GnRHa (P = 0.039) or LNG‐IUS (P = 0.007) were protective against relapse. The risk of recurrence was lower in patients with anterior (P = 0.034) or fundus (P = 0.038) adenomyosis.
Conclusion
Postoperative therapy using GnRHa or LNG‐IUS decreases the long‐term relapse rate in women undergoing conservative surgery.
Synopsis
Postoperative therapy using GnRH agonist or levonorgestrel‐releasing intrauterine system decreases the long‐term relapse rate in women undergoing conservative surgery.
The complex pathogenesis and variable presentation of adenomyosis make it one of the most difficult of the FIGO PALM-COIEN abnormal uterine bleeding to diagnose and treat. Basic clinical parameters ...such as prevalence are difficult to accurately assess because histological confirmation is usually employed; however, because of the access to and accuracy and utilization of transvaginal ultrasound and other advanced imaging techniques such as MRI, noninvasive diagnosis is recognized to be highly accurate. The clinical symptoms of pain, abnormal uterine bleeding, and subfertility are the primary presentations of adenomyosis with increasing data supporting a substantial role of this disease in reducing fecundity and interfering with assisted reproductive interventions. Treatments have been aimed at managing symptoms and improving fertility options. Prior management of hysterectomy is not always desired by women, and with many women having children in their fourth and even fifth decades, it is often not reasonable to consider this radical option.
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