The pathophysiology of endometriosis and adenomyosis: tissue injury and repair

Introduction  This study presents a unifying concept of the pathophysiology of endometriosis and adenomyosis. In particular, a physiological model is proposed that provides a comprehensive explanation of the local production of estrogen at the level of ectopic endometrial lesions and the endometrium of women affected with the disease. Methods  In women suffering from endometriosis and adenomyosis and in normal controls, a critical analysis of uterine morphology and function was performed using immunohistochemistry, MRI, hysterosalpingoscintigraphy, videohysterosonography, molecular biology as well as clinical aspects. The relevant molecular biologic aspects were compared to those of tissue injury and repair (TIAR) mechanisms reported in literature. Results and conclusions  Circumstantial evidence suggests that endometriosis and adenomyosis are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial–myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the mechanism of ‘tissue injury and repair’ (TIAR). This results in the local production of estrogen. With ongoing peristaltic activity, such sites might increase and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization of the uterus with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall ensues. In most cases of endometriosis/adenomyosis, a causal event early in the reproductive period of life must be postulated leading rapidly to uterine hyperperistalsis. In late premenopausal adenomyosis, such an event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life leads to the same extent of microtraumatization. With the activation of the TIAR mechanism followed by infiltrative growth and chronic inflammation, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principle the same pathophysiology. In conclusion, endometriosis and adenomyosis result from the physiological mechanism of ‘tissue injury and repair’ (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary.     

Adenomyosis as a disorder of the early and late human reproductive period

Magnetic resonance imaging (MRI) allows the diagnosis of adenomyosis in vivo with a high sensitivity and specificity. Usually the diagnosis of adenomyosis is obtained from women in their fourth to fifth decade of life. However, recent data suggest that adenomyosis may develop much sooner in life, particularly in women with endometriosis. In order to test these suggestions, MRI of the uterus in 227 women with and without endometriosis was performed and the results were related to the age of the subjects (age groups: 17-24, 25-29, 30-34 and >34 years). The study revealed that the process of the development of adenomyosis, represented by an increased diameter of the dorsal junctional zone of the uterus as the imaging correlative of the invasion of basal endometrium into the junctional zone, had already commenced early in the third decade of life and progressed steadily during the fourth decade in women with endometriosis. Women without endometriosis showed almost no signs of adenomyosis up to the age of 34 years. Surprisingly, parallel in both groups of women, a marked increase in the incidence of adenomyosis could be observed beyond the age of 34 years, thus representing a common phenomenon in the age-related pathophysiological continuum of adenomyosis.     

Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus.

Histologic study of endometriosis and investigation of lymphatic drainage in and out of the uterus were conducted to obtain more information on the histogenesis of endometriosis. Endometriosis is a disease originating from the normal endometrium, specifically from its basal layer. Internal endometriosis (adenomyosis) is caused mainly by direct invasion of the endometrium into the spaces located in the connective tissue of the muscle layer. Serous and ovarian types of endometriosis are frequently found together with adenomyosis. Endometrial fragments in vessels are detected in 4.5% of cases of endometriosis. Observation of serial sections proved that serous endometriosis is caused mainly by continuous or semicontinuous invasion of the tunica muscularis spaces primarily from adenomyosis lesions and partly from the endometrium. Confirmation of lymph flow into the ovary from the uterine body strongly suggests that ovarian endometriosis arises as a consequence of vascular (lymphatic) transport of endometrial fragments from adenomyosis lesions, serous endometriosis lesions, or the endometrium.     

Uterotubal transport disorder in adenomyosis and endometriosis--a cause for infertility

OBJECTIVE: Uterine hyperperistalsis and dysperistalsis are common phenomena in endometriosis and may be responsible for reduced fertility in cases of minimal or mild extent of disease. Since a high prevalence of adenomyosis uteri has been well documented in association with endometriosis, we designed a study to examine whether hyperperistalsis and dysperistalsis are caused by the endometriosis itself or by the adenomyotic component of the disease. DESIGN: A prospective observational study. SETTING: University hospital, Department of Obstetrics and Gynaecology, Division of Reproductive Medicine and Gynaecologic Endocrinology with 300 in vitro fertilisation/intracytoplasmatic sperm injection cycles and 350 intrauterine insemination cycles/year. POPULATION: Forty-one subjects with infertility and with laparoscopically proven endometriosis and patent fallopian tubes. Thirty-five subjects (85%) additionally showed signs of adenomyosis. METHODS: All subjects underwent T2-weighed magnetic resonance imaging (MRI) and hysterosalpingoscintigraphy (HSSG) during the subsequent menstrual cycle. MRI revealed the extent of the adenomyotic component of the disease and the integrity of uterotubal transport capacity was evaluated by HSSG. MAIN OUTCOME MEASURES: Influence of adenomyosis on uterotubal transport capacity in endometriosis. RESULTS: In 35 of the 41 subjects (85%) with endometriosis, signs of adenomyosis were detected using T2-weighed MRI. Two of six (33%) subjects with no adenomyosis (group I) showed dysperistalsis and hyperperistalsis, compared with 14 of 24 (58%) women with focal adenomyosis (group II) and 10 of 11 (91%) women with diffuse adenomyosis (seven showed a failure in transport capacity and two contralateral transport). CONCLUSIONS: Our data suggest that endometriosis is associated with impeded hyperperistaltic and dysperistaltic uterotubal transport capacity. However, adenomyosis is of even more importance, especially when diffuse adenomyosis is detected. Both forms of adenomyosis are commonly found in subjects with mild to moderate endometriosis. We suggest that the extent of the adenomyotic component in subjects with endometriosis explains much of the reduced fertility in subjects with intact tubo-ovarian anatomy.     

Adenomyosis and reproduction

Evidence has been provided that pelvic endometriosis is significantly associated with uterine adenomyosis and that the latter constitutes the major factor of infertility in such conditions. Furthermore, it has become evident that both adenomyosis and endometriosis constitute a pathophysiological and nosological entity. Mild peritoneal endometriosis of the fertile woman and premenopausal adenomyosis of the parous and non-parous woman, as well as adenomyosis in association with endometriosis of the infertile woman, constitute a pathophysiological continuum that is characterized by the dislocation of basal endometrium. Due to the postponement of childbearing late into the period of reproduction, premenopausal adenomyosis might increasingly become a factor for infertility in addition to adenomyosis associated with endometriosis of younger women. In any event, the presence or absence of uterine adenomyosis should be examined in a sterility work-up.     

New aspects in diagnosis and therapy of endometriosis

Endometriosis and adenomyosis show a high prevalence and can be regarded as different symptoms of a unique disease - the dislocation of basal endometrium. Diagnostic methods for detecting adenomyosis are transvaginal sonography (TVS) or T-2-weighed magnetic resonance imaging (MRI). Patients with endometriosis show a significant impairment of utero-tubal sperm transport capacity, which is even increased the stronger the adenomyotic component of the disease is. Adenomyosis can be regarded as a cause for infertility especially in minor and mild forms of endometriosis and is therefore often followed by IVF/ICSI-treatment. Infertility patients with endometriosis should be counselled for intensive infertility treatment. Without a current wish for conception, fertility potential should be preserved by hormonal suppression of uterine peristalsis in order to avoid progression of the disease.     

Duration of dysmenorrhoea and extent of adenomyosis visualised by magnetic resonance imaging

OBJECTIVE: Enlargement of the junctional zone (JZ) on T2-weighted resonance imaging of the uterus has recently been established as the major criterion for adenomyosis in patients with endometriosis. This study was conducted to analyse the extent of adenomyosis using magnetic resonance imaging (MRI) and relate it to the duration of dysmenorrhoea. STUDY DESIGN: This was a prospective study of 70 patients presenting with the complaint of severe dysmenorrhoea. Forty patients (57%) reported dysmenorrhoea as their major complaint and 30 patients (43%) suffered additionally from infertility. Group I (n=40) consisted of patients with dysmenorrhoea of between 1 and 10 years' duration, group II (n=30) consisted of patients with dysmenorrhoea of longer than 11 years' duration. All patients underwent laparoscopy to detect the presence and degree of endometriosis, and all patients underwent T2-weighted resonance imaging of the uterus to detect the extent of adenomyosis by measurement of the "junctional zone". RESULTS: In group I, adenomyosis could be detected via MRI in 21 patients (52.5%), while 19 patients (47.5%) showed no signs of adenomyosis. By contrast, in group II a distinct enlargement of the JZ, as the major radiological criterion of adenomyosis, could be observed in 26 patients (87%), while only 4 patients (13%) revealed no signs of adenomyosis (p=0.04). The mean thickness of the JZ was significantly enlarged in group II (11.07 mm) compared with group I (6.38 mm; p<0.0001). The prevalence of adenomyosis in endometriosis after dysmenorrhoea of more than 11 years' duration was 87%. CONCLUSIONS: In deep infiltrating endometriosis, a correlation between a specific localisation and dysmenorrhoea can often not be found. Recently, endometriosis and adenomyosis have been believed to result from a common uterine disease, the dislocation of the basal endometrium. Our data clearly show that dysmenorrhoea of long duration in patients who have had endometriosis for over a threshold value of 11 years is significantly related to adenomyosis of the uterus. Hence, evaluation of adenomyosis using MRI should become a standard procedure in cases of dysmenorrhoea and endometriosis. Severe dysmenorrhoea of long duration should always focus clinical interest on adenomyosis of the uterus.     

Adenomyosis: the pathophysiology of an oestrogen-dependent disease

Adenomyosis uteri is a common gynaecological disorder that is characterized by the presence of ectopic endometrial glands and stroma in the myometrium. Although adenomyosis and endometriosis are different diseases, both of them grow and regress in an oestrogen-dependent fashion. Polymorphisms in the oestrogen receptor alpha gene are associated with a risk of adenomyosis. Adenomyotic tissue contains steroid receptors as well as aromatase and sulphatase enzymes. Together with the circulating oestrogen, locally produced oestrogens stimulate the growth of tissue mediated by the oestrogen receptors. Oestrogen metabolism, including the expression pattern of aromatase and the regulation of 17beta-hydroxysteroid dehydrogenase type 2 is altered in the eutopic endometrium of women with endometriosis, adenomyosis, and/or leiomyomas compared to that in the eutopic endometrium of women without disease. In addition to the conventional hormonal treatment with gonadotropin-releasing hormone agonists and danazol, the use of steroid-releasing intrauterine devices may be applicable to clinics.     

Antigenic differences between the endometrium of women with and without endometriosis

Serum and peritoneal fluid from 12 women with endometriosis, 4 women with uterine leiomyomata and 6 fertile women without endometriosis (controls) and serum from 4 women with adenomyosis were tested with a passive hemagglutination assay for antibodies against endometrium from all the controls, 8 patients with endometriosis and all patients with uterine leiomyomata and from implants from 8 patients with endometriosis. Serum antibody titers in patients with endometriosis or leiomyomata were significantly higher against endometrial or implant antigens from patients with endometriosis and 2 patients with leiomyomata than those against the controls' endometrium. Peritoneal fluid endometrial antibody titers failed to reflect these antigenic differences. Controls and patients with adenomyosis had low titers of endometrial antibodies in their serum or peritoneal fluid. Antigenic differences appear to exist between the endometrium of patients with endometriosis and that of controls.     

Xanthine oxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis

OBJECTIVE: To investigate the expression of xanthine oxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis. DESIGN: Immunohistochemical identification of xanthine oxidase in endometrial tissues by using polyclonal antibody. SETTING: University hospital. PATIENT(S): Thirty-four women with endometriosis, 34 women with adenomyosis, and 44 fertile control women. INTERVENTION(S): Biopsy samples were obtained from the endometrium throughout the menstrual cycle. MAIN OUTCOME MEASURE(S): Semiquantitative immunostaining (evaluation nomogram) score of endometrial cells. RESULT(S): The level of xanthine oxidase expression in the glandular epithelium of control varied according to menstrual phase, but no such variation in expression was seen in endometriosis. Variation in xanthine oxidase expression was observed during the menstrual cycle in patients with adenomyosis; this variation differed completely from that in controls. Xanthine oxidase expression was found in ectopic endometrial tissue in all cases. The mean evaluation nomogram levels in the glandular epithelium in adenomyosis tissue were as high as those in the early secretory phase in the eutopic endometrium. CONCLUSION(S): Aberrant expression of xanthine oxidase in eutopic and ectopic endometrium appears to play a pathologic role in endometriosis and adenomyosis.     

Adenomyosis and infertility

Today an accurate diagnosis of adenomyosis can be made thanks to progress in imaging techniques: sonography and magnetic resonance imaging (MRI). This has made it possible to clinically correlate the presence of adenomyosis to infertility. At the same time, a series of pathogenetic hypotheses have been presented to explain this correlation. First, the identification of the myometrial junctional zone (JZ) and of its disruption and thickening has been linked to poor reproductive performance mainly through perturbed uterine peristalsis, a phenomenon that originates exclusively from the JZ in the nonpregnant uterus. In addition, a number of biochemical and functional alterations in both eutopic and heterotopic endometrium in women with adenomyosis have now been found to lead to lower receptivity, indicated by the presence of 'implantation marker' defects. In these patients there is also an altered decidualization and abnormal concentrations of intrauterine free radicals. All these abnormalities in the endometrial environment seem to contribute to subfertility. Several attempts have been made to restore fertility in adenomyosis patients, the oldest being gonadotrophin-releasing hormone agonists coupled to conservative surgery. Also, uterine artery embolization and MRI-assisted high-intensity focused ultrasound ablation have been tried with some degree of success.     

Ang-1和Ang-2在子宫内膜异位症及子宫腺肌病中的表达

目的探讨血管生成素-1（Angiopoietin-1,Ang-1）和血管生成素-2（Angiopoietin-2,Ang-2）在子宫内膜异位症及子宫腺肌病发生、发展中的作用。方法采用免疫组织化学SP法检测Ang-1和Ang-2在30例子宫内膜异位症患者（内异症组）和30例子宫腺肌病患者（腺肌病组）在位内膜及26例正常子宫内膜（对照组）中的表达。结果Ang-1和Ang-2在子宫内膜血管内皮细胞、腺上皮细胞和间质细胞中表达,定位于细胞质。Ang-1在内异症在位内膜的表达明显高于对照组（P〈0.05）;Ang-2在内异症和腺肌病在位内膜高表达,与对照组相比,差异有显著性（P〈0.05）。结论Ang-1和Ang-2的高表达可能在子宫内膜异位症及子宫腺肌病的发生发展中起重要作用。     

TNFR1在子宫内膜异位症和子宫腺肌病表达的研究

目的:探讨肿瘤坏死因子受体1(TNFR1)在子宫内膜异位症(内异症)和子宫腺肌病(腺肌病)的表达及在其发病机制中的作用。方法:采用免疫组化SABC法检测33例内异位症患者(内异症组)和40例腺肌病患者(腺肌病组)在位及异位子宫内膜TNFR1的表达,并与20例非内异症(对照组)在位内膜进行比较。结果:内异症组和腺肌病组异位内膜TNFR1的表达水平显著低于其在位内膜和对照组(P<0.05);TNFR1在内异症Ⅰ-Ⅱ期和Ⅲ-Ⅳ期间无显著差异(P>0.05),与内异症r-AFS临床分期亦无直线相关关系(P>0.05);TNFR1在分泌期的表达为内异症、腺肌病异位内膜<其在位内膜<对照组内膜(P<0.05)。结论:异位内膜TNFR1的低表达可能在内异症和腺肌病的发生中起重要作用。TNFR1与内异症严重程度无关。     

Adenomyosis and junctional zone changes in patients with endometriosis

Objectives

To evaluate image findings in the junctional zone (JZ) in patients with endometriosis and correlate with image findings of adenomyosis. To attempt a correlation of the degree of adenomyotic infiltration with the degree of infiltration and stage of endometriosis.

Study design

Magnetic resonance imaging (MRI) of the uterus was performed in 153 women with suspected deeply infiltrating endometriosis and planned surgery, and in a reference group of 129 women without endometriosis, verified during hysterectomy. Changes in the JZ and endometriosis in the pelvis were described in detail. Diagnosis of adenomyosis at MRI was based on optimal criteria derived from the hysterectomy control group. The stage of endometriosis (AFS stage) was determined during surgery.

Results

In the group of women with endometriosis 34.6% had adenomyosis compared with 19.4% in the reference group (p < 0.05). More women with endometriosis (39.9%) had an irregular JZ compared to 22.5% in the reference group (p < 0.01). Among women with severe endometriosis (AFS stage IV) 42.8% had adenomyosis compared to 29.4% in the women with other stages of endometriosis (AFS stages I + II + III) (p = 0.10). More women with severe endometriosis (AFS stage IV) had deeper wall invasion of adenomyosis (p > 0.05) but the presence of deep infiltrative rectovaginal endometriosis and the size of infiltration were not correlated to adenomyosis or depth of infiltration of adenomyosis.

Conclusions

In a group of young women with severe symptomatic endometriosis and planned surgery a systematic evaluation of the JZ revealed that one third had uterine adenomyosis, but the invasive potential of endometrial cells in the uterus and in the peritoneum corresponded only to a limited degree.     

Endometrial carcinoma using GnRH analogues therapy in endometriosis

Endometriosis affects a 10 % of women during their reproductive years. Unequoral statistics concerning the incidence of adenomyosis are not available although a combined occurrence of both diseases is found in a 20 % of cases. The risk that malignancy arises from endometrioid tissue typical for endometriosis is between a 0.3-1 %. 75 % of these malignancies are ovarian cancer in conjunction with pre-existing ovarian endometriosis; less frequently extraovarian malignancies are found. The development of malignancy of adenomyosis is very rarely reported. In this report we present the case of a 35 year old patient who suffered from both, endometriosis and adenomyosis and who underwent a therapy using GnRH analogues. After five months and before the completion of the therapy a hysterectomy with conservation of the ovaries was performed at the request of the patient (carcinophobia). The histology confirmed the diagnosis of adenomyosis and demonstrated the unexpected finding of an endometrium carcinoma. This latter arose from a complex atypical hyperplasia surrounded by hypoplastic endometrium. There is some evidence that suggests a slightly elevated risk of breast and ovarian cancer as well as haematological malignancies amongst patients with endometriosis. However, there does not appear to be an increased risk of endometrial carcinoma. Adipositas leads to an increased risk for the development of endometrial carcinoma due to the increased conversion of testosterone to estrone in fat. The peripheral synthesis of estrone is unaffected by GnRHa-therapy. A progesterone containing HRT should be added to a GnRHa-therapy in overweight patients to prevent the development of endometrial hyperplasia and/or carcinoma. In conclusion a careful indication has to be made for GnRHa-therapy in overweight patients and before and during the therapy high resolution ultrasound scan should be performed to evaluate the endometrium in those patients.     

Contraception and endometriosis

Choosing a contraceptive method for a woman with endometriosis is an uncommon problem because endometriosis is relatively rare and because an estimated 30-50% of women with endometriosis are infertile. Uterine or internal endometriosis or adenomyosis is characterized by a congestive and pseudoinflammatory uterus slightly increased in volume. It must be distinguished from pelvic or external or peritoneo-ovarian endometriosis. Pelvic implants may involve destruction of the ovaries by cysts or their imprisonment in adhesions. They may cause stenosis in the proximal portion of the tubes or entrap them in adhesions. 4 stages of endometriosis have been distinguished according to the significance of the lesions and a scoring system. Stage 4 patients with scores over 70 or with a score over 50 for adhesions have been unable to conceive despite treatment. No contraception is necessary in these cases. The choice of a contraceptive for other patients is conditioned by the features of endometriosis. Endometriosis refers to the abnormal localization of a normal endometrium. The implants are sensitive to estrogen. Each implant behaves like a miniature uterus; the mucus proliferates and bleeds if estrogen secretions are present, or atrophies if not. Endometriosis may be completely asymptomatic, or cause sterility, or be accompanied by pain and metrorrhagia. Several earlier treatments of endometriosis have been abandoned because of side effects. The current treatment of choice is an LHRH analog administered by parenteral injections every 4 weeks to bring about a state of pseudomenopause. The treatment produces a rapid desensitization of the pituitary LHRH receptors and a diminution of gonadotrophins, estrogens, and progesterone. The secondary effects are those of hypoestrogenism: hot flashes, vaginal dryness, and increased bone loss after 6 months of treatment. It is also an expensive medication. Contraception is provided by the treatment itself for the first 6 months. Subsequently, a hydroxyprogesterone derivative such as cyproterone acetate can be used, as can a norpregnane derivative or a combined oral contraceptive with predominant progestin action. Monophasic pills containing norethisterone are also acceptable. In case of metabolic problems, a pill containing gestodene may be used. A vaginal contraceptive should be used in cases of adenomyosis.     

Aberrant expression of glutathione peroxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis

OBJECTIVE:To determine the expression of glutathione peroxidase (GPx) in the eutopic and ectopic endometria during the menstrual cycle in endometriosis and adenomyosis. DESIGN:Immunohistochemical identification of GPx in endometrial tissues identified using the polyclonal antibody. SETTING:Department of obstetrics and gynecology in a university hospital. PATIENT(S):One hundred fourteen women divided into three groups: 33 patients with endometriosis, 34 patients with adenomyosis, and 47 fertile control subjects. INTERVENTION(S):Endometrium biopsied throughout the menstrual cycle. MAIN OUTCOME MEASURE(S):Endometrial cells: semiquantitative immunostaining (evaluation nomogram) score. RESULT(S):The analyses revealed phase-dependent changes of GPx expression in the surface and glandular epithelia in the eutopic endometrium during the menstrual cycle in the fertile controls, i.e., the expression was weak in the early proliferative phase, gradually increased, was most marked in the early secretory phase, and decreased thereafter. The expression of GPx in the eutopic endometrium in endometriosis lost the variation during the menstrual cycle. The expression of GPx in adenomyosis was persistently marked over the control levels throughout the menstrual cycle. CONCLUSION(S):The aberrant expression of GPx in the eutopic endometrium throughout the cycle suggests a pathological role in endometriosis and adenomyosis.     

子宫内膜异位症患者子宫内膜IL-18表达的研究

目的 :研究子宫内膜异位症患者子宫在位内膜和异位内膜IL 18的表达 ,探讨IL 18在内异症发病机制中的意义。方法 :用免疫组化和半定量逆转录聚合酶链反应法检测对照组子宫内膜、子宫腺肌症患者子宫内膜和内异症患者的子宫在位内膜与异位内膜IL 18蛋白的表达位置及其mRNA表达水平。结果 :各组标本IL 18蛋白和mRNA的表达均阳性 ,内异症患者子宫在位内膜与异位内膜的IL 18mRNA表达水平分别为 1.0 5±0 .4 0、0 .77± 0 .39,均低于对照组子宫内膜 (1.6 5± 0 .6 4) ,差异有显著性 (P <0 .0 5 ) ;子宫腺肌症组IL 18mRNA表达水平为 1.6 3± 0 .6 0 ,与对照组子宫内膜IL 18mRNA表达水平差异无显著性。结论 :IL 18可能参与了子宫内膜异位症的发病 ,IL 18mRNA在内异症患者在位和异位内膜的低水平表达 ,可能是影响内异症形成和发展的重要因素之一。     

Uterus didelphys with cervical agenesis associated with adenomyosis,a leiomyoma and ovarian endometriosis. A case report

BACKGROUND: Elevated level of serum CA-125 was detected in a 48-year-old woman who was diagnosed with a lateral fusion defect in association with congenital agenesis of the uterine cervix. This unusual case combined two developmental anomalies of the müllerian duct. CASE REPORT: A 48-year-old woman consulted our outpatient department due to persistent abdominal pain for six months. Bimanual pelvic examination showed absence of the cervix, an anteverted uterus and a 6-cm, left adnexal mass. Ultrasound and computed tomography revealed a uterus didelphys with a 3-cm cystic mass over the right ovary. Serum level of CA-125 was 641.4 U/mL. The patient underwent exploratory laparotomy, and total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Pathology confirmed adenomyosis and a leiomyoma of the uterus with functional endometrium in conjunction with endometriosis of the right ovary. CONCLUSION: Multiple müllerian anomalies associated with adenomyosis and endometriosis should be considered in patients presenting with primary amenorrhea. Thorough evaluation, careful planning, fertility preservation and postoperative outcomes should be reviewed.