JOURNAL TRANSCRIPT

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PROFESSOR MARGIT DUEHOLM (Orcid ID : 0000-0002-2577-7903)

Article type

: State-of-the-art review

Uterine adenomyosis and infertility, review of reproductive outcome after in vitro fertilization and surgery

Running headline: Adenomyosis and infertility

Margit Dueholm

Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark

Corresponding author: Margit Dueholm Department of Gynecology and Obstetrics, Aarhus University Hospital, Palle Juhl Jensensvej 100, 8200 Aarhus N, Denmark Mail: [email protected]

Conflict of interest None

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/aogs.13158 This article is protected by copyright. All rights reserved.

Abstract This review includes: a) analysis of the clinical studies evaluating reproductive outcome and adenomyosis, and b) a review of studies on reproductive outcome and surgical treatment options for adenomyosis. Strict diagnostic criteria and classification of disease are needed for an image diagnosis of adenomyosis. Studies of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) populations and women with surgically treated deep endometriosis suggested that adenomyosis has a negative impact on reproductive outcome, although there are substantial variations between studies. Little data are available on the relation between the extent of disease and impact on reproductive outcome, but a correlation appears to exist. Case series seem to confirm a positive effect of gonadotropin-releasing hormone analog treatment and surgery on reproductive outcome, but there are no controlled trials. Evidence is impaired by the poor quality of many studies, deficient strict image diagnosis, and the absence of a classification of the extent of disease. Selection of the most optimal evidencebased treatment options for adenomyosis in the fertility clinic is difficult because of a lack of evidence regarding the relation between fertility and the degree and composition of adenomyosis. Adenomyosis may reduce implantation so severely that surgical or other treatment options should be recommended, but the benefit of these treatment options needs to be verified. Referral of women with adenomyosis and recurrent miscarriage and repeated failure of assisted reproductive technology to centers with a special interest in adenomyosis research and treatment may be critical.

Keywords: adenomyosis, infertility, assisted reproduction, pregnancy, obstetric outcome, surgery

Key message: Reproductive outcome seems to be reduced in women with adenomyosis, but data on any effective treatment to improve reproduction is limited. Surgery could be effective, but should only be performed in centers specializing in adenomyosis research and treatment.

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Abbreviations: AD

adenomyosis

ART

assisted reproductive technology

IVF

in vitro fertilization

ICSI

intracytoplasmic sperm injection

TVS

transvaginal ultrasonography

3D-TVS

3D-ultrasonography

MRI

magnetic resonance imaging

JZ

junctional zone

JZmax

maximal thickness of junctional zone

PR

pregnancy rate

Introduction Adenomyosis (AD) is regarded a disease of the endo-myometrial junction defined by the presence of heterotopic endometrial glands and stroma in the myometrium. Migration of endometrial cells into the myometrium is accompanied by a varying degree of muscular hypertropia. AD should be understood as a two-component disease consisting of an element of ectopic endometrial glands and stroma and a second element of muscular change (hypertropia, hyperplasia, and fibrosis). The diagnosis of AD is made by histopathology. The increased resolution of transvaginal ultrasonography (TVS), 3D-ultrasonography (3D-TVS) and magnetic resonance imaging (MRI) has made it possible to perform an image diagnose of AD, and to clearly display the endo-myometrial junction. The inner myometrium adjacent to the endometrium, or junctional zone (JZ), is normally displayed as a thin hypoechoic zone by TVS and a low signal band adjacent to the endometrium by MRI.

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Adenomyosis of the uterus is most often diagnosed in the classical form in the fourth or fifth decades of life, based on the classical symptoms of dysmenorrhea and menorrhagia. The classical form of AD is described without endometriosis. However, recent studies have revealed that AD can the coexistence with endometriosis in younger women, indicating a common pathogenesis (1), and AD has been suggested to cause implantation failure in younger women with endometriosis (2). Infertility is a less frequent complaint in the classic form, but because more women delay their pregnancy until their late 30s or 40s, the relation between AD and infertility is becoming increasingly relevant. The impact of AD on fertility is evaluated by imaging. This review will analyze the relation between infertility and AD and review studies on reproductive outcome and surgical treatment options for AD in infertile patients.

Material and methods: We conducted a PubMed search using the keywords: AD OR adenomyoma OR junctional zone AND infertility OR assisted reproduction, IVF, pregnancy OR obstetric outcome, AD AND treatment (surgery, treatment, GnRH, gonadotropin-releasing hormone). In all, 726 abstracts were reviewed, and articles on the subject were retrieved, read, and searched for additional references, resulting in 277 articles being retrieved and indexed. Studies on fertility outcome and AD and surgery for AD were systematically retrieved. Data on fertility outcome and AD were displayed by funnel plots and a simple pooled analysis (fixed model), see Figure 1. In the presence of heterogenecity (I2 ≥50%), pooled values for random effects models are given in the figure legend. No sensitivity or regression analysis or analysis of study quality was performed because a meta-analysis including most of the studies has already been done (2, 3).

Image diagnosis of adenomyosis Studies of AD and fertility are built on an imaging diagnosis without histologic verification. A great variation in the interpretation and use of image criteria is a large confounder in these studies. In a general gynecologic clinic, a single diagnostic ultrasound criterion was present in 21% of women, while three were seen in 14% (4). In women with at least four sonographic

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criteria of AD (8.4% of the women), there was a relation between the numbers of sonographic criteria and the symptoms of menorrhagia (5). This important study indicates the presence of a high number of unspecific image changes in the myometrium which are not AD and underlines the importance of strict criteria for image diagnosis. Image features of AD comprise features of heterotopic endometrial tissue and accompanying myometrial hypertrophy. TVS, 3D-TVS, and MRI features of AD (6) are given in Table 1. Signs of ectopic endometrium are highly specific, while signs of muscular changes are less specific both by TVS and MRI (7). Changes in the JZ can be visualized by MRI or 3D-TVS, and JZ thickness and irregularity are signs of AD. The efficiency of 3D-TVS has been shown in a single study to be slightly more efficient than 2D-TVS for the diagnosis of AD (8). The relative weight of the different features in establishing a correct diagnosis remains unclear, but more than one criterion and often 3 criteria are needed for an image diagnosis of AD, and the uterus should always be searched for clear features of heterotopic endometrium (9, 10). Studies with histopathologic correlation suggested that AD is strongly suspected when the JZ measures at least 12 mm in thickness on MR images (7, 10, 11), but others have used a maximal thickness of 10 mm (JZmax) as a cutoff value beyond which JZ AD is assumed(12). In a review by Champaneria et al.(13) that included only studies of high quality with microscopic verification, the pooled sensitivity and specificity with 95% confidence limits (95% CI) for transvaginal ultrasound were 72% (65–79) and 81% (77–85), respectively, and for MRI were 77% (67–85) and 89% (84–92), respectively. Thus, the use of imaging gives 23–28% false negative results and 11–19% false positive results in highly selected symptomatic women scheduled for hysterectomy. The use of imaging for the diagnosis of AD in an infertile population has clear shortcomings. Image characteristics of AD and the diagnostic efficiency of imaging techniques may be different in infertile populations in which the proportion of women with minimal disease may be more pronounced.

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Junctional zone Smooth muscle changes in the JZ may precede AD. These changes could be regarded as stage 0 AD, with microtraumas in the endo-myometrial boarder that may develop into AD. The smooth muscle change in the JZ may be seen as a disease in itself, an endometrial−subendometrial myometrium unit disruption(14), and Gordts (15) proposed that the junctional changes with a maximum JZ thickness ≥8 mm and 10 mm) on MRI was reported in 79% of women with laparoscopic evidence of peritoneal endometriosis (12) . Three other studies (19-21) reported lower prevalence’s of 27%, 35%, and 38%, respectively, using strict JZ changes for the diagnosis of AD, as explained in Table 1. Thus, AD seems to be present in one-third of women with surgically treated endometriosis. Moreover, the presence and depth of infiltration of AD was related to the extent of endometriosis (20). Muscular peristalsis in the JZ is important in the transport of oocyte and This article is protected by copyright. All rights reserved.

sperm. Uterine contractions are hormone dependent and may be visualized and assessed by ultrasound and seem to affect implantation by assisting in sperm transport (22). Muscular changes in the JZ may reflect an altered peristalsis (23). Dysperistalsis was demonstrated in women with diffuse AD and endometriosis, and a thickened JZ was related to dysperistalsis (23).

Effect of adenomyosis on reproductive outcome Many endometrial receptivity markers are changed in the adenomyotic endometrium (1, 24, 25). Although none of these have proven to be predictive of implantation in humans. No studies have examined natural conception in women with AD, but a negative influence of AD on spontaneous conception is seen in baboons, even in the absence of endometriosis. There is a strong correlation between AD and endometriosis in baboons. (26)

Extent of JZ change related to outcome Imaging allows the diagnosis of JZ changes. In a study by Youm et al., the presence of an increased myometrial thickness without signs of AD was related to lower birth rates. The increased myometrial thickness was most likely attributed to a thickened JZ, which in turn affected fertility. Pregnancy rates in women with AD were lower than in these women without AD (27). In a prospective study, 152 women had MRI prior to in vitro fertilization (IVF) (28). An increase in JZ thickness was significantly correlated with implantation failure at IVF. The pregnancy rate (PR) in the group with average JZ thickness (AJZ) 7 mm was 63% vs 26%. In the group with JZmax 10 mm, PR was 63% vs 14%. Implantation failure rate was 96% in patients with an average JZ thickness greater than 7 mm AND a maximal JZ superior to 10 mm, versus 38% in other patient groups. These studies indicate an increase in adverse implantation outcome in relation to the extent of JZ change and AD. Moreover, changes in the JZ even with a thickness