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Cracking the Enigma of Adenomyosis

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 39866

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Prof. Dr. Sun-Wei Guo

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1. Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
2. Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
Interests: endometriosis; adenomyosis
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Dear Colleagues,

Adenomyosis is a common gynecological disease with an enigmatic pathogenesis and pathophysiology. Despite its high prevalence and negative impact on the quality of life in women with adenomyosis, it is an under-funded and under-investigated disease, with a total number of PubMed-indexed publications less than 1% of that on breast cancer. As a result, its clinical management poses a big challenge.

In the last 5-6 years, the landscape for clinical management of adenomyosis has been changing rapidly. The use of dienogest, the approval of GnRH antagonists, the advent of revolutionary surgical procedures, and various ablation methods—high-intensity focused ultrasound (HiFu), radiofrequency, and microwave, and the experimental demonstration that iatrogenic uterine procedures can increase the risk of development of adenomyosis. These have provided gynecologists with more options, but also produced areas of confusion.

It is time to take stock of these new developments and see how we can best use these new discoveries. In addition, knowledge gaps exist and should be identified. This Special Issue will invite leading experts on epidemiology, pathogenesis, pathophysiology, imaging diagnostics, surgery, and medical treatment to contribute to this Special Issue.

Prof. Dr. Sun-Wei Guo
Guest Editor

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Keywords

adenomyosis
diagnosis
management
pathogenesis
pathophysiology
surgery

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Related Special Issue

Cracking the Enigma of Endometriosis in Journal of Clinical Medicine (2 articles)

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Research

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9 pages, 1521 KiB

Open AccessArticle

Laparoscopic Adenomyomectomy under Real-Time Intraoperative Ultrasound Elastography Guidance: A Case Series and Feasibility Study

by Yoshiaki Ota, Kuniaki Ota, Toshifumi Takahashi, Yumiko Morimoto, Soichiro Suzuki, Rikiya Sano and Mitsuru Shiota

J. Clin. Med. 2022, 11(22), 6707; https://doi.org/10.3390/jcm11226707 - 12 Nov 2022

Cited by 5 | Viewed by 5181

Abstract

Background: This study aimed to examine the clinical characteristics of 11 patients undergoing laparoscopic adenomyomectomy guided by intraoperative ultrasound elastography and this technique’s feasibility. Patients and Methods: Eleven patients undergoing laparoscopic adenomyomectomy using ultrasound elastography for adenomyosis at Kawasaki Medical School Hospital in Okayama, Japan between March 2020 and February 2021 were enrolled. Operative outcomes included operative time, operative bleeding, resected weight, operation complications, percent change in hemoglobin (Hb) values, and uterine volume pre- and postoperatively. Dysmenorrhea improvement was evaluated by changes in visual analog scale (VAS) scores pre- and 6- and 12-months postoperatively. Results: The median operative time and bleeding volume was 125 min (range, 88–188 min) and 150 mL (10–450 mL), respectively. The median resected weight was 5.0 g (1.5–180 g). No intraoperative or postoperative blood transfusions or perioperative complications were observed. The median changes in uterine volume, Hb value, and VAS score were −49% (−65 to −28%), −3% (−11 to 35%), and −80% (−100 to −50%), respectively. The median follow-up period post-surgery was 14 months (7–30 months). Adenomyosis recurrence was not observed in the patients during the follow-up period. Conclusions: Laparoscopic adenomyomectomy using ultrasound elastography guidance is minimally invasive and resects as many adenomyotic lesions as possible. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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10 pages, 2244 KiB

Open AccessArticle

Brain Morphological and Functional Changes in Adenomyosis with Pain: A Resting State Functional Magnetic Resonance Imaging Study

by Xue Jiao, Ming Yuan, Qiuju Li, Yufei Huang, Miaomiao Ji, Jing Li, Shumin Yan, Hao Sun, Xinyu Wang, Zangyu Pan, Qianhui Ren, Dawei Wang and Guoyun Wang

J. Clin. Med. 2022, 11(18), 5286; https://doi.org/10.3390/jcm11185286 - 7 Sep 2022

Viewed by 2242

Abstract

The absence of clinically objective methods to evaluate adenomyosis-associated pain and the poor understanding of its pathophysiology lead to treatment limitations. We conducted a resting-state functional magnetic resonance imaging study with 49 patients with pain-related adenomyosis and 30 pain-free controls to investigate brain morphological alterations and regional dysfunctions in patients with pain-related adenomyosis. These patients had significantly higher scores for anxiety and depression than the control group (p < 0.05). They also had a lower gray matter volume (GMV) in the bilateral insula, left angular gyrus, precuneus, left inferior temporal gyrus, and left postcentral gyrus (p < 0.05, AlphaSim corrected). Similarly, decreased voxel-mirrored homotopic connectivity was observed in the bilateral insula, posterior cingulate cortex, middle frontal gyrus, and postcentral gyrus in the adenomyosis patient group (p < 0.05, AlphaSim corrected). Regional homogeneity showed significant differences mainly in the bilateral cerebellum, left inferior frontal gyrus, medial prefrontal cortex, and posterior cingulate gyrus. Correlation analysis showed that the degree of depression in patients with adenomyosis was negatively correlated with the GMV of the left angular gyrus. The results show that these patients exhibited changes in multiple brain regions associated with pain as well as emotion perception and processing. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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11 pages, 5397 KiB

Open AccessArticle

The Prevalence and Clinical Impact of Adenomyosis in Pregnancy-Related Hysterectomy

by Michele Orsi, Edgardo Somigliana, Fulvia Milena Cribiù, Gianluca Lopez, Laura Buggio, Manuela Wally Ossola and Enrico Ferrazzi

J. Clin. Med. 2022, 11(16), 4814; https://doi.org/10.3390/jcm11164814 - 17 Aug 2022

Cited by 2 | Viewed by 2886

Abstract

Background: The epidemiology of adenomyosis has been traditionally based on patients undergoing hysterectomy for gynecological indications, while its prevalence among hysterectomies performed for obstetric complications is unknown. The aim of this study was to assess the prevalence and clinical impact of adenomyosis diagnosed through histology among women undergoing pregnancy-related hysterectomy (PH). Methods: This was a retrospective cohort study. Women who delivered at a tertiary care regional obstetric hub in Milan between 2009 and 2020 were reviewed to identify cases of PH. Histopathological reports of surgical specimens were examined. Cases with adenomyosis were compared to those without adenomyosis for baseline characteristics, obstetric history and outcomes. Results: During the study period there were 71,061 births and a total of 130 PH, giving a PH incidence of 1.83 per 1000 deliveries. Adenomyosis cases were 18, giving a prevalence of 13.8%. Adenomyosis was associated with placenta previa (77.8 vs. 45.5%, p = 0.01), chorionamnionitis (27.8 vs. 5.4%, p = 0.008), lower gestational age at birth (32 ± 4.6 vs. 35.5 ± 3.6 weeks’ gestation, p = 0.0004), and intrauterine fetal demise among twin pregnancies (50 vs. 4.5%, p = 0.048). Conclusion: Adenomyosis entails a relevant impact on obstetric and perinatal outcomes related to PH. More evidence is needed on the clinical relevance of an ultrasonographic diagnosis of adenomyosis before conception. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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10 pages, 1479 KiB

Open AccessArticle

Anemia-Associated Platelets and Plasma Prothrombin Time Increase in Patients with Adenomyosis

by Qiao Lin, Tiantian Li, ShaoJie Ding, Qin Yu and Xinmei Zhang

J. Clin. Med. 2022, 11(15), 4382; https://doi.org/10.3390/jcm11154382 - 28 Jul 2022

Cited by 9 | Viewed by 2197

Abstract

Patients with adenomyosis are hypercoagulable and often accompanied by anemia, but the specific changes in anemia-related coagulation parameters are still unclear. This study investigated the changes in and influencing factors of coagulation parameters related to anemia in patients with adenomyosis (AM). The coagulation parameters, including platelet count (PC), plasma prothrombin time (PT), activated partial prothrombin time (APTT), thrombin time (TT) and fibrinogen (FB), and hemoglobin (Hb), were measured in patients with adenomyosis (229 cases in AM group), uterine leiomyoma (265 cases in LM group), and undergoing tubal anastomosis (142 cases in the control group). The age of the control group was younger than that of the AM group and the LM group. Compared with the AM and LM groups, the uterus size of the control group was smaller; the AM group was larger than the LM group. The Hb concentration of the AM group was lower than that of the LM and control groups. Compared with the LM and control groups, PC increased and TT shortened in the AM group. APTT in the AM group was shorter than in the control group, and PT was longer than in the LM group. After adjustment using multiple logistic regression analysis, adenomyosis was correlated with Hb concentration (or = 0.971, 95% CI 0.954–0.988, p < 0.001), PC (or = 1.006, 95% CI 1.002–1.011, p = 0.004), PT (or = 3.878, 95% CI 2.347–6.409, p < 0.001), age (or = 1.062, 95% CI 1.013–1.114, p = 0.013), and uterine size (or = 1.103, 95% CI 1.011–1.203, p = 0.028). Correlation analysis showed that PC (r = −0.309) and PT (r = −0.252) were negatively correlated with anemia. The increase in Hb-related PC and PT in patients with adenomyosis indicates that the timely and early detection of coagulation parameters is needed for patients with severe anemia, older age, and larger uterine volume. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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10 pages, 1530 KiB

Open AccessArticle

Long-Term Pregnancy Outcomes of Patients with Diffuse Adenomyosis after Double-Flap Adenomyomectomy

by Yong Zhou, Li Shen, Yuan Wang, Mengjia Yang, Zhengyun Chen and Xinmei Zhang

J. Clin. Med. 2022, 11(12), 3489; https://doi.org/10.3390/jcm11123489 - 17 Jun 2022

Cited by 9 | Viewed by 2813

Abstract

Although many studies show that patients with diffuse adenomyosis who underwent fertility-sparing surgery can have a successful pregnancy, their pregnancy outcomes are still controversial. The objective of this study was to determine long-term pregnancy outcomes and possible influencing factors after double-flap adenomyomectomy for patients with diffuse adenomyosis. A total of 137 patients with diffuse adenomyosis who underwent double-flap adenomyomectomy between January 2011 and December 2019 were studied, and correlations between pregnancy outcomes and clinical data, including age and junctional zone measured by magnetic resonance imaging (JZ_max-A), were analyzed. The results show that 56 patients (40.9%, 56/137) had 62 pregnancies, including 35 natural pregnancies and 27 assisted reproduction pregnancies, after operation. A univariate regression analysis showed that the pregnancy outcomes were related to age at surgery, visual analog scale (VAS) score of preoperative dysmenorrhea, parity experience, length of infertility, and postoperative JZ_max-A. A multivariate regression analysis showed that age at surgery, VAS score of preoperative dysmenorrhea, and postoperative JZ_max-A were the independent indicators correlated with pregnancy outcomes. A receiver operating characteristic curve analysis showed that postoperative JZ_max-A was the most valuable indicator for predicting pregnancy outcomes. Cumulative pregnancy rates during the first 3 years were 70.1% and 20.9% in the postoperative JZ_max-A ≤ 8.5 mm and the postoperative JZ_max-A > 8.5 mm groups, respectively. In conclusion, double-flap adenomyomectomy could improve fertility for diffuse adenomyosis, and postoperative JZ_max-A might be a promising indicator for predicting pregnancy outcomes. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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6 pages, 1022 KiB

Open AccessArticle

Angle of Uterine Flexion and Adenomyosis

by Anjeza Xholli, Umberto Scovazzi, Ambrogio Pietro Londero, Giulio Evangelisti, Elena Cavalli, Maria Giulia Schiaffino, Ilaria Vacca, Francesca Oppedisano, Mattia Francesco Ferraro, Giorgio Sirito, Filippo Molinari and Angelo Cagnacci

J. Clin. Med. 2022, 11(11), 3214; https://doi.org/10.3390/jcm11113214 - 4 Jun 2022

Cited by 7 | Viewed by 4226

Abstract

The aim of this study was to assess the prevalence of adenomyosis in symptomatic women in relation to the angle of flexion of the uterus. A total of 120 patients referring to our Chronic Pelvic Pain Center were prospectively enrolled. Each woman scored menstrual pain, intermenstrual pain, and dyspareunia on a 10 cm visual analogue scale and underwent a clinical examination and transvaginal ultrasound. MUSA criteria were used for the diagnosis of adenomyosis. The angle of flexion of the uterus on the cervix was categorized as <150° (75% of cases), between 150° and 210° (6.7% of cases) and >210° (18.3% of cases). Adenomyosis was diagnosed in 76/120 women (63.3%). In women with adenomyosis, the VAS of intermenstrual pain was higher than in women without adenomyosis (4.04 ± 3.79 vs. 2.57 ± 3.34; p < 0.034). The angle of uterine flexion >210° was more prevalent in women with than without adenomyosis (25.0% vs. 6.8%; p < 0.015). The odds ratio of suffering from adenomyosis markedly increased in the presence of an angle of uterine flexion >210° (OR 5.8 95% CI 1.19, 28.3; p > 0.029). The data indicate that the ultrasound-estimated angle of uterine flexion >210° is related to a higher prevalence of adenomyosis. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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11 pages, 840 KiB

Open AccessArticle

Higher Risk of Anxiety and Depression in Women with Adenomyosis as Compared with Those with Uterine Leiomyoma

by Ni Li, Ming Yuan, Qiuju Li, Miaomiao Ji, Xue Jiao and Guoyun Wang

J. Clin. Med. 2022, 11(9), 2638; https://doi.org/10.3390/jcm11092638 - 7 May 2022

Cited by 6 | Viewed by 2538

Abstract

The main symptoms of adenomyosis may adversely affect physical and mental health and quality of life (QOL). However, studies are few on this topic. This study evaluated the effect of adenomyosis on anxiety, depression, and QOL. Participants with adenomyosis (n = 90) or leiomyoma (n = 59) completed questionnaires, including the visual analog scale (VAS) for pain, Hospital Anxiety and Depression Scale (HADS), and Short Form (SF)-36. HADS anxiety and depression positive rates, physical (PCS) and mental (MCS) component summary scores, and eight subscale scores of SF-36 were compared between the two groups. Among patients with adenomyosis, the incidence of anxiety symptoms was 28.9% (control group, 10.2%; OR = 3.589, 95% CI: 1.375–9.367), with 10% of patients showing moderate-to-severe symptoms. The incidence of depressive symptoms was 14.4% (control group, 3.4%; OR = 4.812, 95% CI: 1.044–22.168). The case group had significantly lower PCS and MCS scores than the control group. In patients with adenomyosis, being employed (OR = 6.393, 95% CI: 1.153–35.440) and perianal pain (OR = 25.419, 95% CI: 2.504–258.024) were risk factors for anxiety, and perianal pain (OR = 15.208, 95% CI: 3.050–75.836) was a risk factor for depression. Compared with leiomyoma, adenomyosis is associated with a higher risk of anxiety and depression, with a poorer QOL. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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Review

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17 pages, 2175 KiB

Open AccessReview

In Search of an Imaging Classification of Adenomyosis: A Role for Elastography?

by Sun-Wei Guo, Giuseppe Benagiano and Marc Bazot

J. Clin. Med. 2023, 12(1), 287; https://doi.org/10.3390/jcm12010287 - 30 Dec 2022

Cited by 9 | Viewed by 3615

Abstract

Adenomyosis is a complex and poorly understood gynecological disease. It used to be diagnosed exclusively by histology after hysterectomy; today its diagnosis is carried out increasingly by imaging techniques, including transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). However, the lack of a consensus on a classification system hampers relating imaging findings with disease severity or with the histopathological features of the disease, making it difficult to properly inform patients and clinicians regarding prognosis and appropriate management, as well as to compare different studies. Capitalizing on our grasp of key features of lesional natural history, here we propose adding elastographic findings into a new imaging classification of adenomyosis, incorporating affected area, pattern, the stiffest value of adenomyotic lesions as well as the neighboring tissues, and other pathologies. We argue that the tissue stiffness as measured by elastography, which has a wider dynamic detection range, quantitates a fundamental biologic property that directs cell function and fate in tissues, and correlates with the extent of lesional fibrosis, a proxy for lesional “age” known to correlate with vascularity and hormonal receptor activity. With this new addition, we believe that the resulting classification system could better inform patients and clinicians regarding prognosis and the most appropriate treatment modality, thus filling a void. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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27 pages, 1316 KiB

Open AccessReview

Pathogenesis of Human Adenomyosis: Current Understanding and Its Association with Infertility

by Khaleque N. Khan, Akira Fujishita and Taisuke Mori

J. Clin. Med. 2022, 11(14), 4057; https://doi.org/10.3390/jcm11144057 - 13 Jul 2022

Cited by 33 | Viewed by 8518

Abstract

The aim of this review article was to summarize our current understanding on the etiologies and pathogenesis of human adenomyosis and to clarify the relative association between adenomyosis and infertility. The exact pathogenesis of adenomyosis is still elusive. Among different reported concepts, direction invagination of gland cells from the basalis endometrium deep into myometrium is the most widely accepted opinion on the development of adenomyosis. According to this concept, endometrial epithelial cells and changed fibroblasts, abnormally found in the myometrium in response to repeated tissue injury and/or disruption at the endometrium-myometrium interface (EMI), elicit hyperplasia and hypertrophy of the surrounding smooth muscle cells. In this review, a comprehensive review was performed with a literature search using PubMed for all publications in English and Japanese (abstract in English), related to adenomyosis and infertility, from inception to April 2021. As an estrogen-regulated factor, hepatocyte growth factor (HGF) exhibits multiple functions in endometriosis, a disease commonly believed to arise from the functionalis endometrium. As a mechanistic basis of gland invagination, we investigated the role of HGF, either alone or in combination with estrogen, in the occurrence of epithelial-mesenchymal transition (EMT) in adenomyosis. Aside from microtrauma at the EMI, metaplasia of displaced Müllerian remnants, differentiation of endometrial stem/progenitor cells within the myometrium and somatic mutation of some target genes have been put forward to explain how adenomyosis develops. In addition, the possible role of microRNAs in adenomyosis is also discussed. Besides our knowledge on the conventional classification (focal and diffuse), two recently proposed classifications (intrinsic and extrinsic) of adenomyosis and the biological differences between them have been described. Although the mechanistic basis is unclear, the influence of adenomyosis on fertility outcome is important, especially considering the recent tendency to delay pregnancy among women. Besides other proposed mechanisms, a recent transmission election microscopic (TEM) study indicated that microvilli damage and an axonemal alteration in the apical endometria of human adenomyosis, in response to endometrial inflammation, may be involved in negative fertility outcomes. We present a critical analysis of the literature data concerning the mechanistic basis of infertility in women with adenomyosis and its impact on fertility outcome. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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28 pages, 1994 KiB

Open AccessReview

Unveiling the Pathogenesis of Adenomyosis through Animal Models

by Xi Wang, Giuseppe Benagiano, Xishi Liu and Sun-Wei Guo

J. Clin. Med. 2022, 11(6), 1744; https://doi.org/10.3390/jcm11061744 - 21 Mar 2022

Cited by 10 | Viewed by 4115

Abstract

Background: Adenomyosis is a common gynecological disorder traditionally viewed as “elusive”. Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power. Methods: PubMed was exhaustively searched using the phrase “adenomyosis and animal model”, “adenomyosis and experimental model”, “adenomyosis and mouse”, and “adenomyosis and rat”, and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner. Results: Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial–myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill’s causality criteria. Other theories only partially satisfy Hill’s criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis. Conclusions: EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis. Full article

(This article belongs to the Special Issue Cracking the Enigma of Adenomyosis)

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