International Journal of Environmental Research and Public Health Review Adenomyosis and Infertility—Review of Medical and Surgical Approaches Maria Szubert 1,* , Edward Koziróg 1, Olga Olszak 2, Klaudia Krygier-Kurz 1, Jakub Kazmierczak 1 and Jacek Wilczynski 1 1 Clinic of Surgical and Oncologic Gynecology, 1st Department of Gynecology and Obstetrics, Medical University of Lodz, 90-419 Lodz, Poland; [email protected] (E.K.); [email protected] (K.K.-K.); [email protected] (J.K.); [email protected] (J.W.) 2 Clinic of Perinatology, 1st Department of Gynecology and Obstetrics, Medical University of Lodz, 90-419 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-426804722 or +48-604402786; Fax: +48-426860471 Abstract: The aim of this review is to clarify the relative association between adenomyosis and infertility and the possible treatment for an infertile patient. Although adenomyosis is detected more often in women of late reproductive age, its influence on pregnancy rates is important, especially considering the tendency to delay pregnancy among women in developed countries. In this article, we present a critical analysis of the literature data concerning the impact of adenomyosis on fertility. The possible effects of treatment on the pregnancy rate will also be discussed. We conducted a literature search; publications from Pubmed, Embase and Cochrane databases published from 1982 to 2019 were retrieved using terms ’adenomyosis and infertility’ and ’adenomyosis and pregnancy Citation: Szubert, M.; Koziróg, E.; outcomes’, extensively studied in the aspects of diagnosis, pathogenesis of infertility and possible Olszak, O.; Krygier-Kurz, K.; Kazmierczak, J.; Wilczynski, J. treatment methods. Molecular studies have given deep insight into the pathogenesis of adenomyosis Adenomyosis and Infertility—Review in the recent few years, but there is a huge discrepancy between in vitro studies and praxis. Oral of Medical and Surgical Approaches. contraceptive pills, anti-prostaglandins, oral or parenteral progestins, danazol and gonadotrophin- Int. J. Environ. Res. Public Health 2021, releasing hormone (GnRH) analogues have all been used to control menstrual pain and menorrhagia 18, 1235. https://doi.org/10.3390/ in women with adenomyosis, but they temporarily suppress the menstrual cycle. Additionally, ijerph18031235 endometrial ablation and hysterectomy used to alleviate pain caused by adenomyosis exclude pregnancy planning. The development of imaging techniques—ultrasound and MRI—enables Academic Editors: the diagnosis of adenomyosis with very high accuracy nowadays, but the methods of treatment Wioletta Zukiewicz-Sobczak, mentioned above have not given satisfactory results in women planning pregnancy. For these Paulina Wojtyla-Buciora, patients, the high-intensity-focused ultrasound method (HIFU) and combined treatment before Izabela R ˛ackaand Andrzej Wojtyla assisted reproductive techniques can prove beneficial in adenomyosis patients. Received: 19 December 2020 Accepted: 26 January 2021 Keywords: adenomyosis; infertility; GnRH; in vitro fertilisation Published: 30 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. The aim of this article was to provide readers with the newest information useful in the management of infertility in adenomyosis patients. Adenomiosis, well-described at the end of the 19th century, still remains a mysterious disease with severe implications on fertility. We conducted a literature search—publications from Pubmed, Embase and Cochrane Copyright: © 2021 by the authors. databases published from 1982 to 2019 were retrieved using terms ‘adenomyosis and Licensee MDPI, Basel, Switzerland. infertility’ and ‘adenomyosis and pregnancy outcomes’. Data of this search are provided in This article is an open access article Figure1. We focused on all aspects of infertility in adenomyosis: Symptoms, pathological distributed under the terms and background, diagnostics and possible management. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Environ. Res. Public Health 2021, 18, 1235. https://doi.org/10.3390/ijerph18031235 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2021, 18, 1235 2 of 12 Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW 2 of 13 Figure 1. Process of data extraction. 2. Definition Definition and Symptoms Adenomyosis is is defined defined as as an an invasion invasion of ofthe the endometrium endometrium into into the uterine the uterine myome- my- triumometrium,, which which results results in an inenlargement an enlargement of the ofuterus, the uterus, formation formation of adenom of adenomyoticyotic tumou tu-rs, profusemours, profusemenstrual menstrual and inter and-menstrual inter-menstrual bleeding bleeding and recurrent and recurrent pain pain.. Microscopically Microscopically ec- topicectopic nonneoplastic, nonneoplastic, endometrial endometrial glands glands and and stroma stroma surrounded surrounded by the by hypertrophic the hypertrophic and hyperplasticand hyperplastic myometrium myometrium are n areoted noted.. The prevalence of adenomyosis fluctuates fluctuates between 5 and 70 70%% [1]. [1]. Before the age of 40 years,years, thethe diseasedisease affects affects 2 2 in in 10 10 women, women, whereas whereas between between 40 and40 and 50 years, 50 years the, incidence the inci- denceincreases increases to 8 in to 10 8 in women 10 women [2]. However,[2]. However the, incidencethe incidence of adenomyosis of adenomyosis is difficultis difficult to toestablish establish due due to theto the lack lack of a of unified a unified definition definition and diagnosticand diagnostic criteria criteria based based on noninvasive on nonin- vasivediagnostic diagnostic tests [ 3test]. Theres [3]. There are no are pathognomonic no pathognom clinicalonic clinical features features for adenomyosis, for adenomyosis, nor norlaparoscopic laparoscopic criteria criteria that that could could be implemented be implemented for thefor diagnosisthe diagnosis [4]. [4]. InIn fact, adenomyosis was previously diagnosed in premenopausal women only on thethe basis of pathological examinationexamination after hysterectomy [[5,6].5,6]. Nowadays, the diagnosis isis based on imaging techniques such as transvaginal ultrasound scan (US) and magnetic resonance imaging (MRI) [7]. [7]. In In one third of cases,cases, adenomyosisadenomyosis isis asymptomatic.asymptomatic. The most common clinical symptoms ar aree menorrhagia (up to 50% of patients), dysmenorrhea (30%) and metrorrhagia (20%),(20%), with other medical conditions such as enlarged uterus and infertilityinfertility [2,6]. [2,6]. Adenomyosis may may be be accompanied by by other mild o oestrogen-dependentestrogen-dependent benign benign dis- dis- oordersrders such as endometriosisendometriosis (70 (70%),%), uterine fibroidsfibroids (50%) and endometrialendometrial hyperplasia (35%). In thethe retrospectiveretrospective analysisanalysis of of 945 945 patients patients who who underwent underwent hysterectomy, hysterectomy, a signifi- a sig- nificantcant positive positive correlation correlation was was found found between between the progression the progression of adenomyosis of adenomyosis and history and his- of prior abortion, history of previous pregnancies and occurrence of leiomyoma. By contrast, tory of prior abortion, history of previous pregnancies and occurrence of leiomyoma. By there was no correlation with smoking, normal delivery, caesarean section, endometrial contrast, there was no correlation with smoking, normal delivery, caesarean section, en- hyperplasia or ovarian endometriosis [8]. dometrial hyperplasia or ovarian endometriosis [8]. 3. Pathogenesis 3. Pathogenesis The pathogenesis of adenomyosis is still unclear. It may develop de novo from a metaplasticThe pathogenesis transformation of adenom of theyosis embryological is still unclear. pluripotent It may develop mullerian de novo remnants. from a met- The aplasticsecond theory,transformation suggested of bythe Bergeron embryologic et al.,al ispluripotent an invasion mullerian of the basal remnants. endometrium The second into theory,the myometrium suggested through by Bergeron an altered et al. or, is absent an invasion JZ (junctional of the basal zone—the endometrium area representing into the myometriumthe internal myometrium) through an al [tered9]. The or invaginationabsent JZ (junctional and intramyometrial zone—the area spreading representing may the be internal myometrium) [9]. The invagination and intramyometrial spreading may be due Int. J. Environ. Res. Public Health 2021, 18, 1235 3 of 12 due to higher oestradiol receptor expression in the adenomyotic foci. Another hypothesis formulated by Leyendecker et al. concerns ’auto-traumatisation’ of the uterus which leads to the TIAR (Tissue Injury And Repair) mechanism as the main cause of adenomyosis [10]. According to the authors, high intrauterine pressure, especially during menstruations, can cause a rupture of the archimyometrium mainly in the cornual region of the uterus. The TIAR mechanism causes a vicious cycle of hyper-estrogenic activity and expression of P450 aromatase. The TIAR mechanism can also occur after multiple D and C procedures (dilatation and curettage). Many macromolecules such as hormones, cytokines and antigens might play a role in the pathogenesis