{"paper_id":"d0c67510-61b5-4561-9a63-1089699e7a66","body_text":"Synopsis\nThe levonorgestrel intrauterine system was more effective than megestrol acetate in \ntreating atypical endometrial hyperplasia in women who declined hysterectomy, especially \nthose with moderate/severe obesity, with fewer adverse effects. Prolonging the therapy to \n12 months for persistent cases seemed safe and improved the complete regression rate.\n1/12https://ejgo.org\nABSTRACT\nObjective: To compare the efficacy of the levonorgestrel intrauterine system (LNG-IUS) \nversus megestrol acetate (MA) in inducing complete regression among women with atypical \nendometrial hyperplasia (AEH) who declined hysterectomy.\nMethods: In this single-center, open-label randomized controlled trial, we included 148 \nwomen with AEH who declined hysterectomy. We randomized participants to receive either \ndaily oral MA 160 mg (n=74) or apply LNG-IUS (n=74) and scheduled their follow-up by \nendometrial sampling at 3, 6, 9, 12, 18, and 24 months. The success rate and duration until \ncomplete regression were the primary outcomes.\nResults: The mean duration until complete regression was 5.52 months (95% confidence \ninterval [CI]=4.85–6.18) for the LNG-IUS group versus 6.87 months (95% CI=6.09– 7 .64) for \nthe megestrol group (log-rank test p-value=0.011). The cumulative regression rate after 12 \nmonths was 91.9% with the LNG-IUS versus 77% with MA (p=0.026). Weight gain in the MA \ngroup vs LNG-IUS group after one year (4.7±4 kg vs. 2.7±2.6 kg, 95% CI=0.89–3.12; p=0.001) \nand after two years of therapy (7 .8±5.1 kg vs. 4.1±2.9 kg, 95% CI=2.29–5.06; p<0.001).\nConclusion: Compared to MA, the LNG-IUS was more efficacious in treating AEH in women \nwho declined hysterectomy, especially those with moderate/severe obesity, with fewer adverse \neffects and less weight gain. Extending therapy to 12 months for persistent cases would \nimprove regression rates with reasonable safety. Alternate hysteroscopic and office sampling \nseemed convenient for follow-up.\nTrial Registration: ClinicalTrials.gov Identifier: NCT04385667\nKeywords: Intrauterine Devices, Progesterone-Releasing; Megestrol Acetate;  \nAtypical Endometrial Hyperplasia; Uterine Bleeding\nReceived: Oct 5, 2023\nRevised: Dec 18, 2023\nAccepted: Feb 11, 2024\nPublished online: Feb 22, 2024\nCorrespondence to\nHytham Atia\nObstetrics & Gynecology Department, Faculty \nof Medicine, Zagazig University, 27th Abdel \nMoaty Street, Zagazig 44514, Egypt.\nEmail: hythamatia@gmail.com\n© 2024. Asian Society of Gynecologic \nOncology, Korean Society of Gynecologic \nOncology, and Japan Society of Gynecologic \nOncology\nThis is an Open Access article distributed \nunder the terms of the Creative Commons \nAttribution Non-Commercial License (https://\ncreativecommons.org/licenses/by-nc/4.0/) \nwhich permits unrestricted non-commercial \nuse, distribution, and reproduction in any \nmedium, provided the original work is properly \ncited.\nORCID iDs\nAmr A. Alnemr \nhttps://orcid.org/0000-0001-8057-735X\nOla A. Harb \nhttps://orcid.org/0000-0002-4396-3101\nHytham Atia \nhttps://orcid.org/0000-0002-4013-9491\nTrial Registration\nClinicalTrials.gov Identifier: NCT04385667\nConflict of Interest\nNo potential conflict of interest relevant to this \narticle was reported.\nOriginal Article\nAmr A. Alnemr ,1  Ola A. Harb ,2  Hytham Atia  1\n1 Obstetrics & Gynecology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt\n2 Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt\nThe efficacy of the levonorgestrel \nintrauterine system versus oral \nmegestrol acetate in treating atypical \nendometrial hyperplasia: a superior \nrandomized controlled trial\nJ Gynecol Oncol. 2024 Sep;35(5):e62\nhttps://doi.org/10.3802/jgo.2024.35.e62\npISSN 2005-0380·eISSN 2005-0399\n\nAuthor Contributions\nConceptualization: A.A.A., A.H.; Data \ncuration: A.A.A.; Formal analysis: H.O.A., A.H.; \nInvestigation: A.A.A., H.O.A.; Methodology: \nA.A.A., A.H.; Software: A.H.; Supervision: A.H.; \nValidation: H.O.A.; Writing - original draft: \nA.H.; Writing - review & editing: A.A.A., A.H.\nINTRODUCTION\nEndometrial hyperplasia is an uneven proliferation of the endometrium with an increased \ngland-to-stroma ratio compared to the normal proliferative endometrium [1 ]. It is a precursor \nfor endometrial carcinoma, especially when atypia is present. Simple or complex atypical \nendometrial hyperplasia (AEH) is associated with a higher incidence of malignant progression \nin 15%– 75% [ 2 ] or concurrent malignancy in approximately one-third of cases [3 ].\nHysterectomy is the recommended treatment for AEH, especially for postmenopausal \nwomen. Although this approach saves women from the risk of disease progression and \nhidden concurrent malignancy, it would be unsuitable for premenopausal women seeking \nfertility preservation. This group of women who wish to have children is steadily expanding \nbecause of the current tendency to delay first conception [4 ]. These women retaining their \nuteri for future fertility would try child-bearing at least once before opting for a hysterectomy. \nIn addition, intraoperative and postoperative risks are predicted in such a population with a \nhigher prevalence of diabetes mellitus, obesity, and metabolic syndrome [5 ,6 ].\nIn recent years, conservative strategies have indicated considerable feasibility and safety as \nfertility-sparing options [7 ]. Progestagen therapy is one option used to treat selected women \nwith endometrial cancer and AEH who desire to preserve fertility or have severe medical \ncomorbidities, precluding immediate surgery. The megestrol acetate (MA) and levonorgestrel \nintrauterine system (LNG-IUS) are the most commonly used progestagen regimens [8 -10 ].\nLNG-IUS would provide better compliance to therapy as a single application and is predicted to \nbe associated with fewer adverse effects due to lower serum progestagen levels. However, there is \nlimited clinical evidence to prove its efficacy and safety as a conservative treatment for AEH [11 ].\nThe study’s main goal was to compare the efficacy of the LNG-IUS and MA regarding the \nability and duration to produce complete regression for cases with AEH. Secondary goals \nincluded a comparison of the incidence of failure rate, recurrence rate, risk of excessive \nweight gain, and thromboembolic and metabolic complications.\nMATERIALS AND METHODS\n1. Study setting\nOur study was an open-label superior randomized controlled trial primarily comparing \nLNG-IUS to MA regarding their efficacy in achieving complete regression of AEH. Before \nthe start of recruitment, we obtained institutional approval from the Institutional Review \nBoard of the Faculty of Medicine, Zagazig University, Zagazig, Egypt (registration number: \nZU-IRB# 4119/13-06-2018, renewed 13-06-2020). We registered the trial at ClinicalTrials.gov \nwith registration number NCT04385667  (09/05/2020). The study setting was the Obstetrics \n& Gynecology Department of Zagazig University Hospitals, Zagazig, Egypt. It is the leading \nhealth facility that serves Egypt’s third most populous governorate (Sharqia Governorate, \n8 million population). The Obstetrics & Gynecology Department has a subspecialized \ngynecologic oncology unit and receives referrals from different facilities in the governorate \nand the neighboring governorates.\n2/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\n\nWe recruited women with a tissue diagnosis of simple or complex hyperplasia with atypia \nand declining hysterectomy as the standard disease management and requested conservative \nmanagement either for fertility preservation or to avoid surgical intervention starting May \n20, 2020. All women received detailed counseling that the ideal treatment for their cases was \nhysterectomy and that we cannot exclude the possibility of progression to or coexistence of \nendometrial cancer. We also counseled them regarding the beneficial value, disadvantages, \nand risks of both LNG-IUS and MA. Then, we obtained written informed consent for the \nrefusal of hysterectomy and their acceptance to participate in the study.\nThe inclusion criteria were women with a confirmed tissue diagnosis of AEH who were \nwilling to preserve their uterus and accept both methods of planned hormonal therapy. The \nexclusion criteria were patients with evidence of concurrent endometrial cancer and simple \nor complex hyperplasia without atypia.\n2. Sample size calculation\nWe calculated the sample size using G power software version 3.10 (Heinrich-Heine-Universität \nDüsseldorf Impressum Kontakt Druckversion) and an online sample size calculator (https://\nclincalc.com/stats/samplesize.aspx). Gallos et al. [12 ] reported an atypical hyperplasia \nregression rate of 90% with LNG-IUS compared to 69% with oral progestagen therapy. We \nestimated the least required sample size to detect this difference: 114– 128 women divided into \nboth groups, with an alpha error of 0.05, a power of 80%, and a one-to-one allocation ratio. The \nauthors collected 148 cases to afford the possibility of a 10% dropout of participants.\nWe produced the simple random sequence using the random sequence generator method on \nthe website https://www.random.org/sequences, with a one-to-one allocation ratio into two \nseparate columns for either group. The randomization/allocation process was concealed using \nsequentially sealed opaque envelopes. We labeled each envelope with a serial number. Inside, \nit had a card mentioning the type of intervention. Once we obtained allocation, we did not \nchange it. We documented the patient’s identification on the intervention card for follow-up.\nWomen in the LNG-IUS arm had an IUS releasing 20 µg of levonorgestrel daily (Mirena ®; \nBayer Schering Pharma AG, Berlin, Germany). The MA arm received oral MA (Bausch & \nLomb, Kingston, UK) 160 mg daily in divided doses.\nWe scheduled endometrial sampling for all study patients 3, 6, 9, 12, 18, and 24 months after \nthe start of allocated therapy to evaluate the response [1 ]. Samples taken at 6, 12, and 24 \nmonths of therapy were under hysteroscopic guidance. Multiple specimens were taken from \ndifferent aspects of the uterine cavity, and the LNG-IUS was left in place for women in this arm. \nWe took the remaining scheduled samples (at 3, 9, and 18 months) using a Pipelle endometrial \nsampler. With negative pressure and opening against the endometrium, we moved the Pipelle \nmultiple times circularly. While maintaining negative pressure, we removed the Pipelle from \nthe uterine cavity. We repeated this process more than once to ensure a sufficient specimen.\nAn expert pathologist examined all slides to monitor the response to therapy over \nsurveillance. We defined the response with every examination as complete regression \n(complete absence of atypia and hyperplasia), partial regression, persistence (no evidence of \nregression or progression), progression to endometrial cancer, and recurrence (recurrence \nof AEH after complete regression). In addition, serial transvaginal ultrasound follow-up was \nperformed at every visit to evaluate the endometrial thickness as part of the follow-up.\n3/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\n\nWe collected participants’ demographic data, including age, parity, history of infertility, \npretherapy weight and body mass index, menopausal state, and symptomatic bleeding. \nWe also collected the primary and secondary study outcomes, including regression rate, \nduration until regression, persistence rate, recurrence rate, time until recurrence, and serial \nendometrial thickness. Finally, we searched for the side effects of therapy, including one- and \ntwo-year posttherapy body weight and body mass index (BMI) changes, thromboembolism, \nbreakthrough bleeding, uncontrolled diabetes, and hypertension.\n3. Statistical methods\nStatistical analysis was performed using IBM SPSS version 25 (IBM Corp., Armonk, NY, USA). \nWe adopted an intention-to-treat analysis of the data of all study participants. Kolmogorov–\nSmirnov and Shapiro–Wilk tests were used to test the normality of the distribution of the \nnumerical data. Normally distributed data are presented as the mean ± standard deviation, \nand between-group differences were calculated using independent samples t tests. Skewed \ndata are presented as the median and interquartile range, and between-group differences \nwere calculated nonparametrically using the Mann–Whitney U test. Categorical data are \npresented as numbers and percentages (%), and between-group differences were calculated \nusing the χ2  test or Fisher’s exact test. A Kaplan–Meier plot was used to detect the survival \ndifference between both groups. A p-value below 0.05 was considered significant. We \nperformed χ2  post hoc testing after Bonferroni adjustment to estimate the significance of the \ndifference between the glycemic and blood pressure control levels for both groups [13 ].\nRESULTS\nWe recruited 148 women with AEH equally distributed to both arms of the study. Seventy-four \npatients received MA therapy, while the remaining seventy-four had LNG-IUS application. \nAfter the start of the study, 5 participants dropped out of the follow-up. Two women had \nno show in the megestrol arm after three and 6 months of follow-up, and one opted for \nhysterectomy after two months. At the same time, two participants in the LNG-IUS arm \nchanged their minds and opted for a hysterectomy three and 5 months after the start of \ntherapy. The remaining participants completed their 24 months of regular follow-up ( Fig. 1 ).\nBoth groups were comparable regarding their demographic data, including age, weight, \nBMI, parity, menstrual status, and comorbidities in the form of diabetes mellitus and \nhypertension. Most of the study population was premenopausal and was comparably \ndistributed to both groups. Similarly, the study population tended to have moderate obesity \n(BMI, 34.1±4.3 kg/m 2 ) (Table 1 ).\nThe mean duration until achieving complete regression was 5.52 months (95% confidence \ninterval [CI]=4.85–6.18) for the LNG-IUS group versus 6.87 months (95% CI=6.09– 7 .64) for \nthe megestrol group (log-rank test p-value=0.011) ( Table 2 ), with a higher rate in the LNG-\nIUS group than in the megestrol group after six months (73% vs. 52.7%, p=0.036). After \nnine months of therapy, the response rates were 85.1% and 68.9%, respectively (p=0.055). \nThe best outcome was achieved after the completion of twelve months of therapy, with a \nsignificantly higher complete regression rate in the LNG-IUS group than in the megestrol \ngroup (91.9% vs. 77%, p=0.026). A single patient (on the LNG-IUS arm) progressed to have \nendometrioid adenocarcinoma at 6 months sampling and opted for a hysterectomy ( Table 3 ). \nPatients with persistent AEH who completed 12 months of therapy were counseled regarding \n4/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\n\nthe failure of treatment and had a hysterectomy (4 vs. 14), with a total hysterectomy rate for the \nstudy population of 6 versus 15 (p=0.033) ( Table 4 ). After achieving complete regression, none of \nthe patients developed recurrence of hyperplasia until 24 months of therapy during follow-up.\nWe studied the possible relationship between obesity and the response rate to therapy. The \ndegree of obesity negatively impacted the complete regression rate. These findings were for \nthe overall treatment outcome (96.3% for overweight, 90.3% for grade I, 74.2% for grade II, \nand 61.1% for grade III obesity, respectively, p=0.002) and MA arm (93.3%, 86.7%, 66.7%, \nand 45.5%, respectively, p=0.016). In contrast, this impact was less evident in the LNG-IUS \narm (100%, 92.9%, 84.6%, and 85.7%, respectively, p=0.058). The LNG-IUS maintained \nreasonably high efficacy for women with moderate and severe obesity (Table 5 ).\nWomen who received megestrol therapy had significantly higher weight gain than the LNG-IUS \ngroup after 1 year (4.7±4 kg vs. 2.7±2.6 kg, 95% CI=0.89–3.12; p=0.001) and after completing 2 \nyears of therapy (7 .8±5.1 kg vs. 4.1±2.9 kg, 95% CI=2.29–5.06; p<0.001) ( Table 4 ).\nRegarding follow-up of glycemic state, women on MA were more prone to poor control of \ndiabetes, new onset glucose intolerance, and diabetes mellitus compared to the LNG-IUS \ngroup at 3 and 12 months of therapy. Similarly, the MA group showed a higher incidence of \n5/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\nEnrollment\nAllocation\nFollow-up /two.LP/four.LP  months\nIntention-to-treat analysis\nMA (n=/seven.LP/four.LP )\n LNG-IUS (n=/seven.LP/four.LP )\nAllocated to LNG-IUS\n(n=/seven.LP/four.LP)\nRandomized (n=/one.LP/four.LP/eight.LP)\nWomen with tissue diagnosis of\nsimple or complex endometrial\nhyperplasia with atypia (n=/three.LP/eight.LP/seven.LP)\nAllocated to MA /one.LP/six.LP/zero.LP mg daily oral dose\n(n=/seven.LP/four.LP)\nExcluded (n=/two.LP/three.LP/nine.LP)\n· Opted to hysterectomy as the definitive treatment\n· Alternate hysteroscopic and office\nendometrial sampling plus TVS at\n/three.LP, /six.LP, /nine.LP, /one.LP/two.LP, /one.LP/eight.LP and /two.LP/four.LP months.\n· Oral glucose tolerance at /three.LP and /one.LP/two.LP months.\n· Follow-up of glycemic control for diabetics.\n· Follow-up of blood pressure, weight gain,\nand other symptoms.\n· /two.LP patients with no-shows\nafter /three.LP and /six.LP months.\n· /one.LP patient opted for a hysterectomy\nafter /two.LP months.\n· /two.LP patients opted for a hysterectomy\nafter /three.LP and /five.LP months.\nFig. 1.  CONSORT flow diagram for trial recruitment. \nLNG-IUS, levonorgestrel intrauterine system; MA, megestrol acetate; TVS, transvaginal ultrasound.\n\n6/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\nTable 1.  Patient demographic data\nCharacteristics MA group (n=74) LNG-IUS group (n=74) p-value\nAge (yr) 46.1±4.3 46.1±4.1 0.984\nAge group 0.675\n≥40 and <45 years 33 (44.6) 32 (43.2)\n≥45 and <50 years 31 (41.9) 35 (47.3)\n≥50 years 10 (13.5) 7 (9.5)\nWeight (kg) 91.8±7.9 91.1±5.6 0.529\nBMI (kg/m2 ) 34.3 (26.3–46.1) 33.9 (28–46.5) 0.570\nDegree of obesity 0.258\nOverweight (BMI ≥18 and <25) 15 (20.3) 12 (16.2)\nGrade I obesity (BMI ≥25 and <30) 30 (40.5) 42 (56.8)\nGrade II obesity (BMI ≥30 and <35) 18 (24.3) 13 (17.6)\nGrade III obesity (BMI ≥35) 11 (14.9) 7 (9.5)\nParity 2 (0–6) 3 (0–7) 0.106\nAbnormal uterine bleeding 60 (81.1) 58 (78.4) 0.838\nInfertility 14 (18.9) 12 (16.2) 0.666\nMenstrual status 0.848\nPremenopause 57 (77.0) 55 (74.3)\nPostmenopause 17 (23.0) 19 (25.7)\nDiabetes mellitus 18 (24.3) 20 (27.0) 0.851\nHypertension 8 (10.8) 9 (12.2) 0.797\nPretreatment endometrial thickness 14.4±3.1 13.2±2.3 0.013 *\nData are presented as number (percentage), the mean ± standard deviation, and median (interquartile range) as \nappropriate.\nBMI, body mass index; LNG-IUS, levonorgestrel intrauterine system; MA, megestrol acetate.\n*Statistically significant.\nTable 2.  Kaplan-Meier survival curve comparing time to regression of atypical endometrial hyperplasia in \nresponse to both methods of progestational therapy\nProgestin type Means for regression time Log rank (Mantel-Cox) p-value\nEstimate  \n(mo)\nSE 95% CI\nLower bound Upper bound\nMA 6.865 0.395 6.090 7.639 0.011 *\nLNG-IUS 5.519 0.339 4.854 6.184\nOverall 6.176 0.264 5.658 6.694\nLNG-IUS, levonorgestrel intrauterine system; MA, megestrol acetate; SE, standard error.\n*Statistically significant.\nTable 3.  Histopathological and ultrasound response to progestational therapy\nTiming and sampling method Cumulative histopathological response during the follow-up sampling p-value Follow-up endometrial \nthickness (mm)\np-value\nComplete regression Persistence Progression\nMegestrol LNG-IUS Megestrol LNG-IUS Megestrol LNG-IUS Megestrol LNG-IUS\n3 mo (Pipelle) 17 (23) 32 (43.2) 56 (75.7) 41 (55.4) 0 (0.0) 0 (0.0) 0.032 * 11 (8–16) 10 (6–15) 0.003 *\n(Dropped† 1+1)\n6 mo (Hysteroscopic guided) 39 (52.7) 54 (73.0) 33 (44.6) 17 (23.0) 0 (0.0) 1 (1.4) 0.036 * 8 (5–15) 6 (4–10) <0.001 *\n(Dropped† 2+2)\n9 mo (Pipelle) 51 (68.9) 63 (85.1) 20 (27) 8 (10.8) 0 (0.0) 1 (1.4) 0.055 8 (5–13) 6.5 (4–9) <0.001 *\n(Dropped† 3+2)\n12 mo (Hysteroscopic guided) 57 (77) 68 (91.9) 14 (18.9) 3 (4.1) 0 (0.0) 1 (1.4) 0.026 * 7 (4–12) 5 (4–8) <0.001 *\n(Dropped† 3+2)\n18 mo (Pipelle) 57 (77) 68 (91.9) 14 (18.9) 3 (4.1) 0 (0.0) 1 (1.4) 0.026 * 6 (4–9) 5 (4–8) <0.001 *\n(Dropped† 3+2)\n24 mo (Hysteroscopic guided) 57 (77) 68 (91.9) 14 (18.9) 3 (4.1) 0 (0.0) 1 (1.4) 0.026 * 5 (4–8) 5 (4–8) <0.001 *\n(Dropped† 3+2)\nData are presented as numbers (percentage).\nLNG-IUS, levonorgestrel intrauterine system.\n*Statistically significant.\n†Dropped: The number of patients dropped out of follow-up (Megestrol + LNG-IUS, respectively) due to opting for a hysterectomy or a no-show.\n\n7/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\nTable 4.  Complications and morbidities associated with progestational therapy\nVariables MA group (n=74) LNG-IUS group (n=74) p-value\nHysterectomy (due to persistence/progression) 15 (20.3) 6 (8.1) 0.033 *\nPost-hysterectomy histopathological result\nNormal 1 0\nAtypical hyperplasia 15 5\nEndometrial carcinoma 0 1\nWeight after 12 months 96.9±8.3 93.8±5.5 0.009 *\nWeight after 24 months 100±8.7 95.2±5.1 <0.001 *\nWeight gain after 12 months 4.7±4 2.7±2.6 0.001 *\nWeight gain after 24 months 7.8±5.1 4.1±2.9 <0.001 *\nGlycemic control at 3 months of therapy 0.003 * Post-hoc\nNormal 43 (58.1) 53 (71.6)\nControlled pretherapy diabetes 6 (8.1) 15 (20.3) 0.15\nPoorly controlled pretherapy diabetes 8 (10.8) 2 (2.7) 0.32\nNew onset glucose intolerance 11 (14.9) 2 (2.7) 0.03 *\nNew-onset diabetes mellitus 3 (4.1) 0 (0.0) 0.31\nGlycemic control at 12 months of therapy 0.006 * Post-hoc\nNormal 40 (54.1) 50 (67.6)\nControlled pretherapy diabetes 7 (9.5) 15 (20.3) 0.28\nPoorly controlled pretherapy diabetes 7 (9.5) 2 (2.7) 0.33\nNew onset glucose intolerance 9 (12.2) 5 (6.8) 0.25\nNew-onset diabetes mellitus 8 (10.8) 0 (0.0) 0.01 *\nBlood pressure at 6 months of therapy 0.030 * Post-hoc\nNormal 58 (78.4) 63 (85.1)\nControlled pretherapy hypertension 3 (4.1) 8 (10.8) 0.36\nPoorly controlled pretherapy hypertension 3 (4.1) 1 (1.4) 0.91\nNew onset hypertension 7 (9.5) 0 (0.0) 0.02 *\nBlood pressure at 12 months of therapy 0.068 Post-hoc\nNormal 56 (75.7) 60 (81.1)\nControlled pretherapy hypertension 2 (2.7) 8 (10.8) 0.16\nPoorly controlled pretherapy hypertension 4 (5.4) 1 (1.4) 0.50\nNew onset hypertension 9 (12.2) 3 (4.1) 0.20\nBreakthrough bleeding 7 (9.5) 16 (21.6) 0.119\nThromboembolic disorders 1 (1.4) 0 (0.0) 0.541\nData are presented as number (percentage) or mean ± standard deviation.\nLNG-IUS, levonorgestrel intrauterine system; MA, megestrol acetate.\n*Statistically significant.\nTable 5.  Comparison of response rate to therapy according to women’s BMI category\nResponse rate after 12 months of therapy Category according to BMI at the start of therapy p-value\nOver-weight Grade I obesity Grade II obesity Grade III obesity\nThe overall response to therapy 0.002 *\nComplete regression (n=125) 26 (96.3) 65 (90.3) 23 (74.2) 11 (61.1)\nPersistence (n=17) 0 (0.0) 4 (5.6) 7 (22.6) 6 (33.3)\nProgression (n=1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6)\nResponse to Megestrol acetate 0.016 *\nComplete regression (n=57) 14 (93.3) 26 (86.7) 12 (66.7) 5 (45.5)\nPersistence (n=14) 0 (0.0) 3 (10.0) 5 (27.8) 6 (54.5)\nProgression (n=0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)\nResponse to LNG-IUS 0.058\nComplete regression (n=68) 12 (100) 39 (92.9) 11 (84.6) 6 (85.7)\nPersistence (n=3) 0 (0.0) 1 (2.4) 2 (15.4) 0 (0.0)\nProgression (n=1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (14.3)\nBMI, body mass index; LNG-IUS, levonorgestrel intrauterine system.\n*Statistically significant.\n\nnew-onset hypertension at 6 months of treatment than the LNG-IUS group (7 vs. 0, p=0.030). \nWith time, new-onset hypertension was also reported in the LNG-IUS group at 12 months of \ntherapy but still occurred less frequently than in the MA group (3 vs. 9, p=0.068) ( Table 4 ).\nBreakthrough bleeding was reported more frequently in women on LNG-IUS than in those \non MA (21.6% vs. 9.5%, p=0.119). Only one patient receiving megestrol was affected by deep \nvenous thrombosis in the lower limb and received anticoagulation therapy (Table 4 ).\nDISCUSSION\nThe definitive treatment for AEH is a hysterectomy with or without oophorectomy [1 ,14 ]. \nGiven the high risk of concurrence of or progression to cancer endometrium in non-\nresponders, conservative treatment is a medical challenge with ethical considerations. Some \naffected women would decline hysterectomy due to an intense desire to preserve their fertility \nor are unfit for major operative intervention for medical or previous surgical reasons.\nThis randomized controlled trial has provided good evidence of the efficacy of progestagen \ntherapy in treating AEH and compared 2 standard methods of its administration. One day, if \nwe find predictive biomarkers to detect the risk of poor response and progression tendency, \nthis therapy might be a valid alternative for all women wishing to preserve their uteri, not \nonly for an exceptional group [15 ].\nThe median duration until complete regression was six months for both therapy methods. LNG-\nIUS had a significantly higher success rate than MA during all the study phases (73% vs. 52.7% \nand 85.1% vs. 68.9% at 6 and 9 months, respectively) until the results plateaued at 12 months, \nwith a final success rate of 91.9% versus 77%, respectively (p=0.026). None of the responders \ndeveloped a recurrence of AEH during the follow-up (Table 3 ). Previous studies also elicited this \nhigher response rate to LNG-IUS at varying levels. Gallos et al. [16 ] reported a pooled complete \nregression rate with LNG-IUS of 90% versus 69% with oral progestagen in their meta-analysis. \nLeone Roberti Maggiore et al. [17 ] found complete regression in 89.3% of women with AEH \non LNG-IUS, with a median time to regression of 6.7 months. Pal et al. [18 ] reported complete \nregression at 6 months on the LNG-IUS of 80% (95% CI=52–96). A prospective cohort study \nby Novikova et al. [19 ] included 228 women with AEH and reported a complete regression \nrate of 98% with LNG-IUS compared to 87% with medroxyprogesterone acetate. The higher \nbioavailability of levonorgestrel to the endometrium could explain the considerably higher efficacy \nof LNG-IUS reported by us and others. The device steadily provides local levonorgestrel with a \nconcentration multiple times that of oral therapy with minimal systemic concentrations [20 ,21 ].\nWhile prolonging the therapy for up to 12 months for non-responders improved the complete \nregression rate and still seems reasonable and safe, one of the participants in the LNG-\nIUS group (1.4%) had evidence of progression to endometrioid adenocarcinoma grade II \nduring sampling at 6 months of follow-up. The myometrial invasion was less than 50%, and \na radical hysterectomy with lymphadenectomy was performed. Doherty et al. [3 ] reported \nin their meta-analysis a concurrent endometrial cancer with atypical hyperplasia of 32.6% \n(95% CI=24.1%–42.4%) with an annual incidence rate of progression to cancer of 8.2% (95% \nCI=3.9%– 17 .3%). Despite our low incidence of progression, AEH remains a premalignant \nlesion that we should manage cautiously, especially with the lack of markers to predict the \ntendency for progression or to distinguish atypia from low-grade malignancy [ 3 ,15 ].\n8/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\n\nOur follow-up during the study was by endometrial sampling plus transvaginal ultrasound \nevery three months during the first year of therapy and every 6 months during the following \nyear. This frequency aligns with the sampling frequency of 3–6 months reported in multiple \nprevious studies [5 ,17 ,22 ,23 ]. We used hysteroscopic-guided endometrial biopsies alternating \nwith Pipelle office sampling to maintain accuracy at a reasonable cost. Hysteroscopy \nprovides precise and targeted sampling even with focal lesions and LNG-IUS in place and \nwas the preferred method in multiple previous studies [5 ,17 ,19 ,22 ,24 ,25 ]. On the other \nhand, an expert gynecologist performed office sampling using a Pipelle sampler, which was \nmore convenient to patients, with minimal discomfort and cost. Multiple previous studies \nreported a reasonable accuracy of Pipelle sampling, especially with atypical hyperplasia, with \na sensitivity of 70%–97 .8% compared to hysteroscopy/dilatation and curettage [ 22 ,23 ,26 -\n29 ]. Conversely, some questioned the efficacy of office sampling given the small percentage \nof sampled endometrial surface, especially in women with thinned-out endometrium or \nfocal endometrial lesions [22 ,27 ,30 ]. The posthysterectomy histological assessment of \nthe nonresponders was concordant with the preoperative sampling in 13/14 (92.9%). The \nremaining patient specimen showed simple hyperplasia without evidence of atypia. This \nresult is reassuring that our strategy of follow-up sampling was convenient.\nThe degree of obesity negatively impacted the response rate. Women with grade III obesity \nin the MA group reported the lowest complete regression rate (45.5%). LNG-IUS was more \neffective in inducing complete regression for women of the same category (85.7%) ( Table 4 ).  \nThis finding suggests that the LNG-IUS might be more convenient for morbidly obese \nwomen. Obesity and metabolic syndrome are substantial risk factors for endometrial \nhyperplasia and malignancy by various mechanisms, including hyperestrogenism, insulin \nresistance, and different growth factors [31 ]. Ding et al. [5 ] found metabolic syndrome \npredisposing to a delayed regression time (odds ratio=3.1; 95% CI=1.0–5.2; p=0.005). \nGraul et al. [32 ] reported an increased risk of progression with a rising BMI. However, a \nbetter response to therapy was reported by Mandelbaum et al. [33 ] in class III obese women \ncompared to nonobese women.\nRegarding the side effects of therapy, the mean weight gain in the MA group was significantly \ngreater than that in the LNG-IUS group at 1 year (4.7 vs. 2.7 kg, p=0.001) and 2 years of \ntreatment (7 .8 vs. 4.1 kg, p<0.001), respectively. Our study population’s weight gain in both \ngroups was greater than the reported weight gain in most available studies. Cholakian et al. \n[8 ] reported a mean weight gain of 2.95 kg with MA versus 0.5 kg with LNG-IUS after 1 year. \nPark et al. [34 ] reported a mean weight gain of 1.2 kg after 18 months of oral progestagens, \n13.6% had a weight gain of >1 kg per month, and 4.5% had a weight gain of ≥2 kg per month. \nHowever, Güven et al. [35 ] also reported that the median weight gain on MA after 3 months \nwas 4 kg. Similarly, Novikova et al. [ 19 ] reported weight gain exceeding 5 kg in 36% of women \non medroxyprogesterone acetate compared to 12% of women on LNG-IUS. Other studies \nreported weight gain of 0.7–2.9 kg after one year on LNG-IUS as a contraceptive device [ 36 -\n38 ]. The variance in weight gain between our population and other previous studies may be \nexplained by racial differences, lifestyle, dietary habits, and high basal BMI.\nIt is worth mentioning that MA was associated with less control of diabetes and hypertension \nin affected women. Women in the megestrol group also had a higher incidence of new-onset \nglucose intolerance, diabetes mellitus, and hypertension. We could partly explain this finding \nby the high basal BMI, weight gain, and increased appetite induced by MA [39 ].\n9/12https://ejgo.org https://doi.org/10.3802/jgo.2024.35.e62\nLNG-IUS versus megestrol atypical endometrial hyperplasia\n\nThe study’s strengths include the randomized controlled design with a powered sample \nsize for the primary outcome and intention-to-treat analysis. This trial is one of the few \nregistered trials comparing LNG-IUS to MA in treating AEH. We delineated explicit inclusion \nand exclusion criteria, a clear duration of therapy, a cutoff time until treatment failure, and a \nconvenient strategy for sampling and other outcome follow-ups. The lack of a comprehensive \nsurvey of other adverse effects, such as mood changes, headache, and sexual dysfunction, \nlimits our study. Additionally, we did not study the relationship between items of metabolic \nsyndrome, the risk of AEH, and the impact of selected therapy. Although the study lacks a \nlong-term recurrence rate, progression rate, and conception rate follow-up, the authors plan \nto conduct a posttrial follow-up study to assess the therapy’s long-term efficacy.\nProgestational therapy effectively induced complete regression in 84.5% of women with AEH \nwho initially declined hysterectomy. Compared to oral MA, the LNG-IUS showed significantly \nhigher efficacy in inducing complete regression (91.9% vs. 77%), especially in morbidly obese \nwomen. It was associated with substantially less weight gain and better blood pressure and \nglycemic control. It is more convenient with better compliance being a single application \nduring the whole therapy without requiring daily oral doses.\nExtending conservative therapy until 12 months will improve the complete regression rate in \npersistent atypical hyperplasia cases with reasonable safety, given that timely and cautious \nfollow-up is maintained. The alternation between hysteroscopic-guided and Pipelle office \nendometrial sampling seems to be an adequate and balanced follow-up strategy with high \naccuracy and affordable costs.\nThe long-term efficacy of therapy and optimal therapy duration still need further assessment. The \nfuture challenge in this aspect is to find reliable markers to predict the tendency for progression. \nThen, the LNG-IUS would be a reasonable treatment option for all women with AEH.\nCompared to MA, the LNG-IUS was more efficacious in treating AEH in women who declined \nhysterectomy, especially in morbidly obese women, with fewer adverse effects. Extending \ntherapy for 12 months to persistent cases would improve regression rates with reasonable \nsafety. We can alternate between hysteroscopic and office sampling for follow-up.\nACKNOWLEDGEMENTS\nThe authors thank all trial participants who agreed to be enrolled. 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