European Review for Medical and Pharmacological Sciences 2021; 25: 3432-3439 The treatment with Levonorgestrel Releasing Intrauterine System (LNG-IUS) in patients affected by menometrorrhagia, dysmenorrhea and adenomimyois: clinical and ultrasonographic reports F. COSTANZI, M.P. DE MARCO, C. COLOMBRINO, M. CIANCIA, F. TORCIA, I. RUSCITO, F. BELLATI, A. FREGA, G. COZZA, D. CASERTA Department of Surgical and Medical Sciences and Translational Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Rome, Italy Abstract. – OBJECTIVE: Adenomyosis is p=0.025; p=0.014). The blood loss decreased the consequence of the myometrial invasion significantly in both the cohorts (p<0.001) and by endometrial glands and stroma. Transvag- particularly in adenomyotic patients. Pain relief inal ultrasonography plays a decisive role in was observed in all the patients (p<0.001). the diagnosis and monitoring of this patholo- CONCLUSIONS: LNG-IUS can be considered gy. Our study aims to evaluate the efficacy of an effective treatment for managing symptoms LNG-IUS (Levonorgestrel Releasing Intrauter- and improving uterine morphology. ine System) as medical therapy. We analyzed both clinical symptoms and ultrasonograph- Key Words: ic aspects of menometrorrhagia and dysmen- Benign disease of uterus, Dysmenorrhea, Gyne- orrhea in patients with adenomyosis and the cologic imaging, Leiomyomas of the uterus/adeno- control group. myosis. PATIENTS AND METHODS: A prospective co- hort study was carried out on 28 patients suf- fering from symptomatic adenomyosis treat- ed with LNG-IUS. Adenomyosis was diagnosed Introduction through transvaginal ultrasonography by an ex- pert sonographer. A control group of 27 symp- Adenomyosis is a benign gynecological dis- tomatic patients (menorrhagia and dysmenor- ease with a large variety of clinical manifestation; rhea) without a transvaginal ultrasonograph- the most frequent include menorrhagia, metror- ic diagnosis of adenomyosis was treated in the rhagia, dysmenorrhea and chronic pelvic pain1. same way. The two cohorts were compared to Patients can also experience dyspareunia and the efficacy of LNG-IUS on menorrhagia and 2,3 dysmenorrhea. Patients are evaluated at the infertility . Its pathogenesis is still unknown, al- time of LNG-IUS insertion and six months after though many theories have been considered over for: increased uterine volume, globulous uter- the years2. Adenomyosis is histologically defined ine morphology, uterine symmetry, alterations as the ectopic presence of endometrial glands in the junctional zone, heterogeneous myome- and stroma in the myometrium, with consequent trial texture, presence of myometrial cysts, hy- hyperplasia and hypertrophy of the smooth mus- perechogenic lines crossing the myometrium, 4 adenomyomas, menstrual blood loss and dys- cle . Nowadays, a definite diagnosis is still made menorrhea. on a pathological analysis performed on uterine RESULTS: After six months, the uterine vol- specimens. ume decreased significantly in both cohorts Nevertheless, non-invasive image techniques, (p=0.005; p=0.005). Furthermore, uterine sym- such as transvaginal ultrasound (TVS) and mag- metry, visibility of the junctional zone, hetero- netic resonance imaging (MRI), have proven geneity of myometrial texture, presence of myo- helpful in the preoperative diagnosis of adeno- metrial cysts, hyperechogenic lines and adeno- 5-7 8,9 myomas improved in patients affected by ade- myosis disease . Authors who compared the nomyosis (p>0.001; p>0.001; p>0.001; p=0.014; results obtained from TVS and MRI with those 3432 Corresponding Author: Flavia Costanzi, MD; e-mail: [email protected] Role of Levonorgestrel Releasing Intrauterine System (LNG-IUS): clinical reports obtained from histopathology have noticed that Patients and Methods MRI and TVS’s diagnostic efficiency was almost in line. TVS is considered the first choice of im- Patients age modality when investigating adenomyosis; From May 2017 to June 2018 – after obtaining however, MRI may be helpful in increasing the approval of the Ethics Committee (Protocol No. diagnostic performance when TVS provides in- 23957) – 55 patients between 35 and 50 years old definite findings or when dealing with complex with menorrhagia and heavy menstrual bleeding cases with the coexistence of other abnormal- were enrolled from the Gynecology department ities (e.g., myomas and severe endometriosis)10 of Department of Surgical and Medical Sciences sonographic diagnosis of adenomyosis is made and Translational Medicine, Sant’Andrea Uni- when at least three of the following signs are versity Hospital, Sapienza University of Rome, found: increased uterine volume, globulous uter- Rome, Italy. Twenty-eight patients were diag- ine morphology, uterine asymmetry, alterations nosed with adenomyosis, whereas 27 patients did in the junctional zone, heterogeneous myometri- not meet the criteria to be diagnosed with the al texture, myometrial cysts and hyperechogenic same pathology. All included patients had mod- lines crossing the myometrium. To date, there erate or severe symptoms of dysmenorrhea and are not international guidelines for the clinical metrorrhagia. All patients were candidates for and surgical management of the pathology. Hys- therapy with LNG-IUS due to the presence of terectomy is a definite treatment of symptomatic symptoms. patients, but plenty of conservative medical and surgical options can be considered to treat ad- Inclusion criteria were: enomyosis. Adenomyosis, in childbearing age, – no hormonal therapies in the previous six could be managed with a less invasive approach months; like medical therapy or conservative surgery. – no previous diagnosis PID; The results obtained from conventional surgery – no previous or current gynecological tumors are effective for symptom control. Improve ab- (cervix, uterus, ovaries); dominal pain, abnormal uterine bleeding and – did not undergo surgeries of the genital area. improve fertility are the main results of this type of surgery11. Levonorgestrel Releasing Exclusion criteria were: Intrauterine System (LNG-IUS) represents one – could not be treated using LNG-IUS of the medical alternatives in the treatment of – received hormonal therapies in the previous six adenomyosis. This device has been approved months; in Europe as a contraceptive method in 1990; – had/ was having PID; more recently, it has been used to manage men- – had gynecological tumors (cervix, uterus, ova- orrhagia and dysmenorrhea12, abnormal uterine ries); bleeding (AUB), endometrial hyperplasia, ad- – underwent surgeries of the genital area; enomyosis13 uterine fibroids and as a progestin – pregnancy. component in postmenopausal hormone thera- py14. The use of LNG-IUS for five years duration Adenomyosis was diagnosed by an expert so- is motivated by the inhibition of the endometrial nographer when at least 3 of the following signs proliferation induced by the drug, which leads were found at the transvaginal ultrasound (TVS): to a positive impact on dysmenorrhea and heavy – Increased uterine volume; menstrual bleeding. – Globulous uterine morphology; Moreover, because of the local administration – Uterine asymmetry; of the drug (1000 ng/mL intrauterine vs. <0.2 – Alterations in the junctional zone; ng/mL plasmatic), the device is characterized – Heterogeneous myometrial texture; by low metabolic side effects15. Indeed, patients – Presence of myometrial cysts; show excellent tolerance and good compliance – Hyperechogenic lines crossing the myometri- in the majority of cases16,17. With these premises, um and adenomyomas. the objective of this pilot study is to evaluate the efficacy of LNG-IUS as medical therapy to treat All patients were asked for their medical histo- both clinical symptoms (dysmenorrhea and heavy ry and symptoms, including menometrorrhagia, menstrual bleeding in particular) and ultrasono- dysmenorrhea, chronic pelvic pain and dyspareu- graphic aspects of adenomyosis. nia. All patients were adequately informed and 3433 F. Costanzi, M.P. De Marco, C. Colombrino, M. Ciancia, F. Torcia, et al provided written informed consent for inclusion Statistical Analysis in the study and implantation of LNG-IUS. They All data were statistically analyzed using were also asked for providing the results of a the non-parametric Wilcoxon signed-rank test PAP-smear and a vaginal smear done respective- (not-continuous variables) or ANOVA 2x2x2 ly within the previous year and the last month. (continuous variables) using SPSS 24.0 (Statis- They underwent LNG-IUS implantation between tical Product and Service Solution; IBM Corp., the 5th and seventh day of the menstrual cycle. Armonk, NY, USA). Differences were considered Patients were divided into two cohorts, “adeno- significant at a p-value <0.05. First, a Kolmogor- myosis” and “not-adenomyosis”. Both the cohorts ov-Smirnov test was made to study the distribu- were followed up clinically over time and then tion of data. Parametric tests and non-parametric compared to study the efficacy in the absolute tests were respectively conducted to investigate value of LNG-IUS on adenomyosis. the variables. Clinical Follow-Up Ultrasonographic parameters and symptoms Results were registered before starting the treatment and during the clinical follow-up. Follow-up Our study evaluated how parameters changed was conducted at 1, 3 and 6 months from the in 6 months, both in each cohort and between the implantation. Visits were made by the same so- two cohorts. General characteristics of patients are