Etonogestrel-releasing subdermal contraceptive implant: Budget impact analysis based on the Brazilian private healthcare system.

High rates of unplanned pregnancies persist despite pharmacological developments and advancements in contraceptive methods. Here, we demonstrate that the etonogestrel-releasing subdermal contraceptive implant (IMP-ETN) may be an appropriate and cost-effective alternative to levonorgestrel-releasing intrauterine systems (LNG-IUSs) for women in Brazil. For our pharmacoeconomic analysis, we reviewed the literature on IMP-ETN regarding its acceptance, eligibility criteria, choice, relations with age, adverse events and, finally, the unmet need in the fee-for-service private healthcare sector. We considered qualitative observations in combination with quantitative analysis and performed a deterministic sensitivity analysis to investigate whether this technology can be self-sustainable over a period of five years. The target population for this analysis comprised 158,696 women. Compared with the continued use of LNG-IUSs, adopting the IMP-ETN can result in a cost avoidance of $ 7.640.804,02 in the first year and $ 82,455,254.43 in five years. Disseminating information among physicians will promote this change and strengthen the potential cost avoided by private health system payers. These savings can be used to improve other healthcare programs and strategies. Moreover, the principles of care can be promoted by improving and adapting healthcare systems and expanding treatment and follow-up strategies. This would also provide support to women's reproductive rights and improve their quality of life. Our results suggest that the IMP-ETN has a favorable cost-effectiveness profile. Given all its advantages and negative incremental cost impact over a period of five years, the IMP-ETN may be a more favorable alternative to LNG-IUSs. Therefore, it should be offered to beneficiaries with a private healthcare plan. This analysis overcomes previous barriers to the use of cost-benefit models, and our results may help balance decision-making by policymakers, technical consultants, and researchers.

Do COX-inhibitors improve emergency contraception efficacy?

Overview of: Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial [correction appears in Lancet 2023;402:850]. Lancet 2023;402:851-8.

Laparoscopic adenomyomectomy combined with levonorgestrel-releasing intrauterine system is effective for long-term management of adenomyosis.

BACKGROUD: Laparoscopic adenomyomectomy combined with intraoperative placement of levonorgestrel-releasing intrauterine device (LNG-IUS) is a novel conservative surgical procedure for adenomyosis. Our study aimed to compare the efficacy of surgery with or without intraoperative placement of LNG-IUS treatment in adenomyosis. METHODS: We retrospectively reviewed the medical records of adenomyosis patients who received laparoscopic adenomyomectomy from January 2014 to April 2020, finally including 70 patients undergoing surgery-LNG-IUS as group A and 69 patients undegoing surgery only as group B. Risk factors for three-year relapse were analyzed using Cox's multivariate proportional hazard analysis. RESULTS: Visual analog scale and Mansfield-Voda-Jorgensen Menstrual Bleeding Scale scores of group A at 3, 6, 12, 24, and 36 months were significantly lower than those of group B at the corresponding points (P < .001 for both scales). Individuals in both groups showed statistically significant symptom relief. The recurrence rate in group A was significantly lower than that in group B at 36 months after the surgery (2.94% vs. 32.84%, P < .001). A cox proportional hazard model showed that relapse was significantly associated with coexisting ovarian endometriosis (adjusted hazard ratio [aHR], 2.94; 95% confidence interval [CI], 1.33-7.02, P = .015). Patients who received surgery-LNG-IUS had a lower risk of recurrence than those with surgery-alone (aHR, 0.07; 95% CI, 0.016-0.31, P < .001). CONCLUSIONS: Conservative surgery with intraoperative placement of LNG-IUS is effective and well-accepted for long-term therapy with a lower recurrence rate for adenomyosis. Coexistent ovarian endometriosis is a major factor for adenomyosis relapse.

Feasibility and Effectiveness of Hysteroscopic Suture Fixation of the Levonorgestrel-Releasing Intrauterine System in the Treatment of Adenomyosis.

STUDY OBJECTIVE: To evaluate the feasibility and effectiveness of hysteroscopic suture fixation of the levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of adenomyosis. DESIGN: A retrospective case series. SETTING: Two teaching hospitals with the technology of hysteroscopic suture fixation of the LNG-IUS. PATIENTS: The study reviewed 79 adenomyosis patients who received the hysteroscopic suture fixation of the LNG-IUS from January 2021 to May 2022. INTERVENTION: Hysteroscopic suture fixation of the LNG-IUS to the posterior uterine wall with nondissolvable suture. MEASUREMENTS AND MAIN RESULTS: All patients underwent one-year postoperative follow-up to evaluate the LNG-IUS expulsion rate, postoperative efficacy, and side effects. Two patients (2.6%) experienced expulsion of the LNG-IUS at 8 months and 12 months postoperatively, respectively. The visual analog pain scale, pictorial blood loss assessment chart score and carbohydrate antigen 125 markedly decreased after the suture fixation of the LNG-IUS compared with baseline in all patients (p <.001). Hemoglobin increased significantly (p <.001). The most common side effect was irregular bleeding, which accounted for 44.3%. The second common side effect was weight gain, which accounted for 29.2%. The composite effectiveness based on pain and bleeding showed that the effective treatment rates at 1, 3, 6, and 12 months after surgery were 92.4%, 97.4%, 96.2%, and 97.4% respectively. CONCLUSIONS: Hysteroscopic suture fixation of the LNG-IUS to the uterine fundus was associated with low expulsion rates and significantly improved dysmenorrhea and bleeding.

Retail demand for emergency contraception in United States following New Year holiday: time series study.

OBJECTIVE: To estimate the increase in sales of emergency contraception following the New Year's Eve/New Year's Day holiday. DESIGN: Time series analysis using autoregressive integrated moving average (ARIMA) model. SETTING: Traditional (that is, "bricks and mortar") retail outlets-grocery stores, drug stores, mass merchandisers, club stores, dollar stores, and military outlets-in the United States from 2016 to 2022. DATA SOURCE: Marketing data on weekly aggregated sales of items classified as emergency contraception gathered between 2016 and 2022 (n=362). On the basis of dates, weeks were classified as following the New Year holiday (n=6) or not (n=356). MAIN OUTCOME MEASURE: Weekly sales of levonorgestrel emergency contraception per 1000 women of reproductive age in the US population. RESULTS: Sales of levonorgestrel emergency contraception significantly increased after the New Year holiday (0.63 (95% confidence interval 0.58 to 0.69) unit increase per 1000 women aged 15-44). Holidays that share some aspects of the elevated risks of unprotected sexual intercourse with the New Year holiday (Valentine's Day, St Patrick's Day, US Independence Day) were associated with increased sales, albeit to a lesser degree, with respective sales increases per 1000 women aged 15-44 of 0.31 (0.25 to 0.38), 0.14 (0.06 to 0.23), and 0.20 (0.11 to 0.29). Holidays without these expectations (Easter, Mother's Day, Father's Day) were not significantly associated with sales of levonorgestrel emergency contraception. CONCLUSIONS: Increased sales of emergency contraception following the New Year's holiday suggest that this period is associated with increased risks of unprotected vaginal intercourse compared with other holidays. Targeting behavioral risks, prevention strategies to mitigate sexual violence, and improving access to contraception around holidays may limit the risks associated with unprotected vaginal intercourse.

Oral hormonal therapy as treatment option for abnormal uterine bleeding.

BACKGROUND: abnormal uterine bleeding is a very frequent reason for referral to gynaecologists and can deeply influence the quality of life. Once organic causes requiring surgical treatment are ruled out, clinicians should be able to manage these patients conservatively in the most effective way. MATERIALS AND METHODS: a search in PubMed/MEDLINE database was conducted in order to find relevant and recent meaningful sources for this narrative review. RESULTS: LNG-IUS 52 mg is the first-line treatment for non-organic causes. Nevertheless, it could be contraindicated or declined by the patient. Combined oral contraceptives (COC) and progestin-only pills inhibit the hypothalamic-pituitary-ovarian axis, preventing ovulation, and induce endometrial atrophy. Consequently, they are effective in treating AUB. Moreover, brand new pills containing a combination of oestrogens, progestins and GnRH antagonists are now available for the management of AUB related to uterine fibroids. CONCLUSIONS: In daily clinical practice, oral hormonal therapies are convenient and reversible tools to manage AUB when LNG-IUS 52 mg is contraindicated or turn down by the patient. Many oral hormonal therapies are prescribed to treat AUB, but only a few have been approved with this specific indication, therefore further large well-designed studies are necessary in order to compare the efficacy of different pills for treating AUB.

Even though LNG-IUS 52 mg is the first-line treatment for abnormal uterine bleeding, oral hormonal therapies should be effectively managed by gynaecologists in case of contraindications or patient's decline. Contraceptive pills are practical, but further studies are necessary to compare their efficacy and to approve them with the specific AUB indication.

Emergency contraception - A review.

Emergency contraception (EC), or postcoital contraception, is a therapy aimed at preventing unintended pregnancy after an act of unprotected or under-protected sexual intercourse. Options include both emergency contraceptive pills (most commonly containing levonorgestrel or ulipristal acetate) and insertion of an intrauterine device. The aim of this paper is to summarize current evidence surrounding the use of emergency contraceptives and to present an evidence-based approach to EC provision. Emergency contraception is a safe and effective option in preventing unwanted pregnancy, irrespective of age, weight, or breastfeeding status. Efforts should be made to increase their availability, as well as knowledge of these methods, both among patients and healthcare providers.

Rates of medical or surgical treatment for women with heavy menstrual bleeding: the ECLIPSE trial 10-year observational follow-up study.

Background: Heavy menstrual bleeding is a common problem that can significantly affect women's lives until menopause. There is a lack of evidence on longer-term outcomes after seeking health care and treatment for heavy menstrual bleeding. Objectives: To assess the continuation rates of medical treatments and the rates of ablative and surgical interventions among women who had participated in the ECLIPSE trial (ISRCTN86566246) 10 years after initial management for heavy menstrual bleeding in primary care. To explore experiences of heavy menstrual bleeding and influences on treatment for women. Design: This was a prospective observational cohort study, with a parallel qualitative study. Setting: Primary care. Participants: A total of 206 women with heavy menstrual bleeding who had participated in the ECLIPSE trial consented to providing outcome data via a questionnaire approximately 10 years after original randomisation. Their mean age at follow-up was 54 years (standard deviation 5 years). A purposeful sample of 36 women also participated in semistructured qualitative interviews. Interventions: The ECLIPSE trial randomised participants to either the levonorgestrel-releasing intrauterine system (52 mg) or the usual medical treatment (oral tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone, chosen as clinically appropriate by general practitioners and women). Women could subsequently swap or cease their allocated treatment. Main outcome measures: The main outcome measures were rates of ablative and surgical treatments; the rate of continuation of medical treatments; and quality of life using the Short Form questionnaire-36 items and EuroQol-5 Dimensions; women's experiences of heavy menstrual bleeding; and the influences on their decisions around treatment. Results: Over the 10-year follow-up period, 60 out of 206 (29%) women had received a surgical intervention [hysterectomy, n = 34 (17%); endometrial ablation, n = 26 (13%)]. Between 5 and 10 years post trial intervention, 89 women (43%) had ceased all medical treatments and 88 (43%) were using the levonorgestrel-releasing intrauterine system alone or in combination with other oral treatments. More women in the usual medical treatment group had also used the levonorgestrel-releasing intrauterine system than women in the levonorgestrel-releasing intrauterine system group. Fifty-six women (28%) used the levonorgestrel-releasing intrauterine system at 10 years. There was no statistically significant difference in generic quality-of-life scores between the two original trial groups, although small improvements in the majority of domains were seen in both groups across time. Women reported wide-ranging impacts on their quality of life and normalisation of their heavy menstrual bleeding experience as a result of the taboo around menstruation. Women's treatment decisions and experiences were influenced by the perceived quality of health-care interactions with clinicians and their climacteric status. Limitations: Fewer than half of the original 571 participants participated; however, the cohort was clinically and demographically representative of the original trial population. Conclusions: Medical treatments for women with heavy menstrual bleeding can be initiated in primary care, with low rates of surgical intervention and improvement in quality of life observed 10 years later. Clinicians should be aware of the considerable challenges that women with heavy menstrual bleeding experience at presentation and subsequently over time, and the importance and value to women of patient-centred communication in this context. Future work: Any further evaluation of treatments for heavy menstrual bleeding should include long-term evaluation of outcomes and adherence. Trial registration: The original ECLIPSE trial was registered as ISRCTN86566246. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 17. See the NIHR Journals Library website for further project information.

Heavy menstrual bleeding is a common problem that can significantly affect women's lives, yet many women do not seek medical help. Medical treatments, such as tablets and a hormonal coil inserted in the womb, were shown to help women with heavy menstrual bleeding in a previous clinical trial that we conducted, called ECLIPSE. In the ECLIPSE trial, women provided information for 5 years after their treatment started. We planned to continue to ask these women about their periods, their symptoms and quality of life, and the treatments that they chose about 10 years after they first joined the trial. We did this using questionnaires and by interviewing women. We received questionnaires from 206 out of the 490 women (42%) who had participated in the ECLIPSE trial 10 years earlier. Responders were, on average, 54 years old, and half reported that they had reached the menopause. About 3 in 10 women overall had either received a hysterectomy or undergone destruction of the womb lining. Just over one-quarter of women were using the hormonal coil. Quality of life remained improved and was generally higher than that before treatment. There was no big difference in quality of life or in the numbers of women having surgery between those who first used tablets and those who received the coil. Women described the wide-ranging impact of heavy bleeding on their lives and the taboo around periods. Women's experience of good or poor communication with their doctors, and thoughts about fertility and menopause, influenced the treatment choices that they made. Women's quality of life was improved by medical treatments for heavy menstrual bleeding, even as menopause approached, and this shows the importance of these treatments. This research can help doctors and women to make more informed decisions about medical and surgical treatments.

Segmented in vitro fertilization and frozen embryo transfer in levonorgestrel-releasing intrauterine device treated patients with endometrial cancer.

PURPOSE: To evaluate the efficacy of levonorgestrel-releasing intrauterine device (LNG-IUD) during controlled ovarian stimulation (COS) in patients with early-stage endometrioid endometrial cancer (EEC). METHODS: A retrospective study was conducted on patients with stage IA1 EEC who achieved complete response after fertility-sparing treatment from December 2018 to December 2021, with all the women who underwent COS having LNG-IUDs inserted in their uterine cavity. RESULTS: 16 patients were enrolled who underwent 26 COS cycles and average age was 33.19 ± 4.04 years. 12 patients had 19 subsequent frozen-thawed embryo transfer (FET) cycles. Among the other four patients, no embryos were obtained in 1 patient, 1 patient got pregnancy spontaneously with term delivery after COS, 1 patient relapsed before FET, and 1 patient did not receive embryo transfer for personal reason. Among 19 FET cycles, the clinical pregnancy and live birth rates in each ET cycle were 36.84% (7/19) and 26.32% (5/19), respectively. 7 clinical pregnancies resulted in 2 miscarriages (28.6%), and 5 live births (71.4%). Totally 6 patients achieved 7 live births, and the cumulative live birth rate was 37.5% (6/16). Three (18.75%) out of 16 patients relapsed after COS during the follow-up period (31.31 ± 15.89 months) and two of them were initially diagnosed with moderately differentiated EEC. Time interval from COS to relapse was 6.63,11.67 and 16.23 months, respectively. CONCLUSION: The combination of LNG-IUD treatment and segmented IVF may be a viable treatment strategy to improve oncological and reproductive outcomes for patients with early-stage EEC.

Efficacy and safety of different subsequent therapies after fertility preserving surgery for endometriosis: A systematic review and network meta-analysis.

BACKGROUND: Endometriosis (EMT) is a benign and common estrogen-dependent disease. Hormonal therapy improves pain symptoms in most women with EMT. However, in many cases, laparoscopic fertility preservation surgery is considered a common treatment for EMT. The present study aimed to evaluate the efficacy and safety of dienogest, leuprolide, danazol, gestrinone, mifepristone and levonorgestrel intrauterine system (LNG-IUS) in relieving symptoms and delaying the recurrence of EMT cysts after fertility protection surgery. METHODS: We searched PubMed, the Cochrane Library, Web of Science, EMBase, China National Knowledge Infrastructure, VIP Database, China Biology Medicine disc, WanFang Data databases to collect randomized controlled trials (RCT) related to dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS as a follow-up treatment after fertility preserving surgery for EMT. After literature screening, data extraction and quality evaluation, effective rate, recurrence rate, pregnancy rate and adverse reaction rate were used as outcome indicators to evaluate the efficacy and safety of drugs. Evidence networks included in the study were drawn and publication bias was assessed. The drugs most likely to be the best postoperative treatment were explored through mixed comparison of different drugs and efficacy ranking. RESULT: Effective rate: dienogest, leprerelin, gestrinone and LNG-IUS were better than placebo after EMT fertility preservation surgery; dienogest was superior to mifepristone and danazol. LNG-IUS is superior to danazol. LNG-IUS has the highest potential for improving the effectiveness of EMT symptoms. Recurrence rate: the application of dienogest, leuprolide, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was lower than that of placebo; dienogest and LNG-IUS were lower than danazol. The recurrence rate of dinorgestrel was the last place with the highest performance. Pregnancy rate: in the cases with fertility requirements, dienogest and,leuprolide were better than placebo after EMT fertility preservation surgery; dienogest was superior to danazol, gestrinone and mifepristone. Leuprolide is superior to danazol and gestrinone. The first rank of dienogest pregnancy rate was the highest. Adverse reaction rate: the application of dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was higher than that of placebo. After placebo, LNG-IUS had the highest adverse reaction rate. CONCLUSION: For patients after fertility preserving surgery for EMT, the recurrence rate of dienogest was the last place with highest preference. The first rank of dienogest pregnancy was the highest.

A randomized trial comparing the 52-mg levonorgestrel system with combination oral contraceptives for treatment of heavy menstrual bleeding.

BACKGROUND: The levonorgestrel intrauterine system and combined oral contraceptives are the 2 most commonly used nonsurgical treatments for heavy menstrual bleeding in the United States. However, there are limited data on their relative effectiveness and on their impact on bleeding-specific quality of life. OBJECTIVE: This study aimed to compare the effectiveness of the 52-mg levonorgestrel intrauterine system with that of combined oral contraceptives for improving quality of life among individuals who self-report heavy menstrual bleeding. We hypothesized that the levonorgestrel intrauterine system would be more effective than combined oral contraceptives at 6 and 12 months after treatment. STUDY DESIGN: We conducted a pragmatic randomized trial of individuals who self-reported heavy menstrual bleeding. Individuals were eligible if they did not have contraindications to either the levonorgestrel intrauterine system or combined oral contraceptives and were determined to have a nonstructural cause of heavy menstrual bleeding. Eligible and consenting participants were randomly assigned in a 1:1 ratio to receive a 52-mg levonorgestrel intrauterine system or a monophasic 30- or 35-µg ethinyl estradiol-containing combined oral contraceptive. The main outcome was mean change in bleeding-related quality of life, measured by the 20-question Menstrual Bleeding Questionnaire (score range, 0-75) at 6 and 12 months. Differences in group means and confidence intervals for the Menstrual Bleeding Questionnaire score were computed by multivariable linear mixed-effects regression; 24 participants per group were needed to detect a 10-point difference in change in mean Menstrual Bleeding Questionnaire score between individuals treated with the levonorgestrel intrauterine system and those treated with combined oral contraceptives at each follow-up time point. RESULTS: A total of 62 individuals were randomly assigned to treatment (n=29 allocated to levonorgestrel intrauterine system and n=33 allocated to combined oral contraceptives) and included in the intention-to-treat analyses; 19 of 29 received the levonorgestrel intrauterine system and 31 of 33 received combined oral contraceptives. Eleven percent identified as Black or African American and 44% identified as Hispanic or Latina. Participant characteristics were similar among study groups. Bleeding-related quality of life increased in both study arms, as reflected by a significant decrease in Menstrual Bleeding Questionnaire scores beginning at 6-week follow-up. In the main intention-to-treat analyses (n=62), there were no differences in mean change in Menstrual Bleeding Questionnaire scores at 6 months (difference=-2.5; 95% confidence interval, -10.0 to +5.0) or 12 months (difference=-1.1; 95% confidence interval, -8.7 to +6.5). Findings were similar in the subsets of participants with any follow-up visits (n=52) and who completed all follow-up visits (n=42). In the per-protocol analyses (n=47), a significantly greater decrease in Menstrual Bleeding Questionnaire score was observed in the levonorgestrel intrauterine system arm at 6 months after treatment (difference=-7.0; 95% confidence interval, -13.8 to -0.2) but not at 12 months (difference=-4.8; 95% confidence interval, -11.8 to 2.3) compared with the combined oral contraceptive arm. CONCLUSION: No differences in change of bleeding-related quality of life were observed between the levonorgestrel intrauterine system and combined oral contraceptives at 6 or 12 months. Patients should be counseled that the levonorgestrel intrauterine system and combined oral contraceptives are both effective options for improving bleeding-related quality of life.

Transvaginal ultrasound- and laparoscopy-guided percutaneous microwave ablation for adenomyosis has short- and long-term benefits: a single-center study.

OBJECTIVES: Transvaginal ultrasound- and laparoscopy-guided percutaneous microwave ablation (TLPMA) is a minimally invasive alternative technique with low risk, fast recovery and few side effects. We aimed to evaluate the safety and long-term efficacy of TLPMA for treating adenomyosis. METHODS: We included 79 patients with symptomatic adenomyosis who underwent TLPMA and 44 patients with adenomyosis who received the levonorgestrel-releasing intrauterine system (LNG-IUS). We evaluated the role of laparoscopy in TLPMA as well as the short- and long-term effects of TLPMA. RESULTS: The mean age of the 79 patients who underwent TLPMA was 41.8 years. There was no difference in the mean age between the TLPMA and LNG-IUS groups. Laparoscopy could help to separate pelvic adhesions, provide a wide antenna path, and observe the uterine surface and bowel movement. No major complications were found in patients who underwent TLPMA. There was a significant post-treatment reduction in both the uterine and lesion volumes (p < 0.001). After a median follow-up duration of 36 months (range: 1-60 months), the uterine and lesion volumes remained stable. Additionally, most patients remained without dysmenorrhea, which confirms the long-term efficacy of TLPMA. CONCLUSIONS: TLPMA is a feasible, minimally invasive technique for the treatment of adenomyosis, which significantly decreases the uterine and lesion volumes and has a good long-term effect.

Levonorgestrel-releasing intrauterine system effects on metabolic variables in PCOS.

BACKGROUND: We aimed to determine and compare the reproductive hormone level and metabolic of patients with polycystic ovary syndrome (PCOS) when treated with a levonorgestrel-releasing intrauterine system (LNG-IUS). OBJECTIVES: Sixty-four women with PCOS (Group A) and sixty-six healthy women inserted with a LNG-IUS for conception (Group B) were recruited from the Department of Obstetrics and Gynecology in Jinhua Hospital Zhejiang University School of Medicine. METHOD: We compared the general characteristics of the cases between the two groups, including age, body mass index (BMI), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), abdominal circumference (AC) and waist circumference (WC). Each patient was evaluated by transvaginal ultrasonography (TVS) to determine the number of oocytes and ovarian volume, and the intima-media thickness (IMT) of the common carotid artery was measured on an ECG image from the left common carotid artery before and six months, 12 months and 24 months after patients were inserted with the LNG-IUS. Hormone levels (follicle stimulating hormone, luteinizing hormone, serum estradiol and total testosterone), serum insulin, sex hormone binding globulin (SHBG), total cholesterol (TC), high density lipoprotein (HDL), and triglyceride (TG), were evaluated before and six months, 12 months and 24 months after patients were inserted with an LNG-IUS. The levels of testosterone (T) in the non-HA (hyperandrogenemia) group and HA group in PCOS group were compared with the baseline. We also compared cases without insulin resistance in the PCOS group with their baseline. RESULTS: Prior to LNG-IUS insertion, the PCOS group had significantly higher total testosterone levels (p < 0.05), lower HDL levels (p < 0.05), and a greater ovarian volume (p < 0.05) than the control group. Compared to baseline values, there was a significant increase in fasting glycemia at six months after LNG-IUS insertion (p < 0.05). Mean ovarian volume was significantly smaller than the volume prior to LNG-IUS insertion (p < 0.05); LDL and TC were significantly reduced when compared to baseline evaluation in the PCOS group. The remaining variables did not differ significantly during the 24 months follow-up period. The control group did not show any significant changes when compared to the period before LNG-IUS insertion. When the groups were compared after the 24-month follow-up, WC, AC, FSH, LH, T, SHBG, HDL, FINs, FAI and ovarian volume were significantly different when compared between the two groups (p < 0.05) . CONCLUSION: The LNG-IUS is an effective and safe non-surgical device and the use of this system for 24 months did not result in significant changes in the clinical and metabolic variables in women with PCOS and healthy control females.

Systemic Progestins and Progestin-Releasing Intrauterine Device Therapy for Premenopausal Patients With Endometrial Intraepithelial Neoplasia.

OBJECTIVE: To estimate trends in use and outcomes of progestin therapy for premenopausal patients with endometrial intraepithelial neoplasia. METHODS: The MarketScan Database was used to identify patients aged 18-50 years with endometrial intraepithelial neoplasia from 2008 to 2020. Primary treatment was classified as hysterectomy or progestin-based therapy. Within the progestin group, treatment was classified as systemic therapy or progestin-releasing intrauterine device (IUD). The trends in use of progestins and the pattern of progestin use were examined. A multivariable logistic regression model was fit to examine the association between baseline characteristics and the use of progestins. The cumulative incidence of hysterectomy, uterine cancer, and pregnancy since initiation of progestin therapy was analyzed. RESULTS: A total of 3,947 patients were identified. Hysterectomy was performed in 2,149 (54.4%); progestins were used in 1,798 (45.6%). Use of progestins increased from 44.2% in 2008 to 63.4% in 2020 ( P =.002). Among the progestin users, 1,530 (85.1%) were treated with systemic progestin, and 268 (14.9%) were treated with progestin-releasing IUD. Among progestin users, use of IUD increased from 7.7% in 2008 to 35.6% in 2020 ( P <.001). Hysterectomy was ultimately performed in 36.0% (95% CI 32.8-39.3%) of those who received systemic progestins compared with 22.9% (95% CI 16.5-30.0%) of those treated with progestin-releasing IUD ( P <.001). Subsequent uterine cancer was documented in 10.5% (95% CI 7.6-13.8%) of those who received systemic progestins compared with 8.2% (95% CI 3.1-16.6%) of those treated with progestin-releasing IUD ( P =.24). Venous thromboembolic complications occurred in 27 (1.5%) of those treated with progestins; the venous thromboembolism (VTE) rate was similar for oral progestins and progestin-releasing IUD. CONCLUSION: The rate of conservative treatment with progestins in premenopausal individuals with endometrial intraepithelial neoplasia has increased over time, and among progestin users, progestin-releasing IUD use is increasing. Progestin-releasing IUD use may be associated with a lower rate of hysterectomy and a similar rate of VTE compared with oral progestin therapy.

Heavy Menstrual Bleeding Treatment With a Levonorgestrel 52-mg Intrauterine Device.

OBJECTIVE: To evaluate heavy menstrual bleeding treatment outcomes with levonorgestrel 52-mg intrauterine device (IUD) use in participants without body mass index (BMI) or parity restrictions. METHODS: Investigators included participants aged 18-50 years with no pelvic or systemic pathology causing heavy menstrual bleeding at 29 U.S. centers in a prospective trial. Participants had up to three screening cycles with menstrual product collection for alkaline hematin blood-loss measurements. Investigators enrolled those with two menses with blood loss of 80 mL or more (values averaged for baseline blood loss), placed the IUD, and followed participants for up to six 28-day cycles. Participants collected any menstrual products used during cycles 3 and 6 for blood-loss measurement. We evaluated outcomes in participants with at least one follow-up assessment for the primary outcome of median absolute blood-loss change and, secondarily, treatment success , defined as the proportion with a final measured blood loss less than 80 mL and at least 50% reduction from baseline. We evaluated exploratory outcomes of differences in blood-loss changes by BMI and parity using Wilcoxon rank sum test. RESULTS: Of 105 enrolled participants, 47 (44.8%) had obesity (BMI 30.0 or higher) and 29 (27.6%) were nulliparous. Baseline mean blood loss ranged from 73 to 520 mL (median 143 mL, interquartile range 112-196 mL). Eighty-nine (84.8%) had at least one evaluable follow-up evaluation. Participants had median (interquartile range) absolute blood-loss decreases at cycles 3 (n=86) and 6 (n=81) of 93.3% (86.1-97.7%) and 97.6% (90.4-100%), respectively. At cycle 6, participants without obesity (n=43) and with obesity (n=38) had similar median [interquartile range] decreases (97.6% [91.8-100%] and 97.5% [90.3-100%], respectively; P =.89), with comparable findings for nulliparous (n=25) and parous (n=56) participants (97.0% [91.7-99.1%] and 98.1% [89.9-100%], respectively; P =.43). Treatment success occurred in 81.8% (95% CI 74.2-89.4%) of 99 participants, excluding those with no outcomes due to lost to follow-up or consent withdrawal, and did not vary by BMI or parity. The most common adverse events leading to discontinuation were bleeding or cramping (n=6 [5.7%]) and expulsion (n=5 [4.8%]). CONCLUSION: This levonorgestrel 52-mg IUD reduces blood loss by more than 90% over 6 months compared with baseline for most users with heavy menstrual bleeding. FUNDING SOURCE: Medicines360. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03642210.

Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin.

BACKGROUND: Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown, but it is likely multifactorial (eg, impaired angiogenesis, "leaky" fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, antiproliferative, and antiangiogenic properties, which may make it a useful agent for implant-associated bothersome bleeding. OBJECTIVE: This study aimed to evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users. STUDY DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Here, etonogestrel implant users with frequent or prolonged bleeding or spotting were enrolled and randomized to either 600-mg Theracurmin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. The term "frequent" was defined as ≥2 independent bleeding or spotting episodes, and the term "prolonged" was defined as ≥7 consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical examination and negative gonorrhea and chlamydia and pregnancy tests. Enrolled participants initiated study treatment after 3 consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30 days of enrollment, the participants were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner, and spotting was defined as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. The secondary outcomes included total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha level of .05 to demonstrate a 6-day difference between groups. RESULTS: From February 2021 to November 2022, 58 individuals enrolled in the study with 54 participants (93%) completing 30 days of treatment (26 in the curcumin group and 28 in the placebo group). Of note, 1 individual in the curcumin arm did not experience a qualifying bleeding event and, thus, never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups, including length of implant use at study enrollment (placebo, 521±305 days; curcumin, 419±264 days). The study groups did not differ concerning any bleeding-related outcome (mean days without bleeding or spotting: curcumin, 16.7±6.9; placebo, 17.5±4.8; P=.62; mean bleeding-free days: curcumin, 23.4±4.9; placebo, 22.4±4.5; P=.44; bleeding episodes: curcumin, 2.0±0.8; placebo, 2.1±0.8; P=.63). In addition, satisfaction with the implant as contraception and acceptability of bleeding over the study period did not differ by study group (P=.54 and P=.30, respectively). CONCLUSION: Daily use of curcumin did not improve bleeding patterns in users of the etonogestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.

Comparative study of the levonorgestrel intrauterine system and laparoscopic hysterectomy for the treatment of heavy menstrual bleeding in enlarged uteri.

OBJECTIVE: The levonorgestrel intrauterine system treatment prevents 67.7% of surgeries in patients with heavy menstrual bleeding and enlarged uteri. To evaluate the effectiveness of the levonorgestrel intrauterine system in the treatment of patients with heavy menstrual bleeding and an enlarged uterus and to compare satisfaction and its complications with hysterectomy. METHODS: This was a comparative cross-sectional observational study of women with heavy menstrual bleeding and an enlarged uterus. Sixty-two women were treated and followed up for four years. Insertion of the levonorgestrel intrauterine system was performed in Group 1, and laparoscopic hysterectomy was performed in Group 2. RESULTS: In Group 1 (n=31), 21 patients (67.7%) showed improvement in the bleeding pattern, and 11 patients (35.5%) had amenorrhea. Five patients (16.1%) remained with heavy bleeding and were considered to have experienced treatment failure. There were seven expulsions (22.6%); in five patients, bleeding remained heavy, but in two patients the bleeding returned to that of normal menstruation. No relationship was found between treatment failure and greater hysterometries (p=0.40) or greater uterine volumes (p=0.50), whereas expulsion was greater in uteri with smaller hysterometries (p=0.04). There were 13 (21%) complications, seven (53.8%) in the group that underwent insertion of the levonorgestrel intrauterine system (all were device expulsions), and six (46.2%) in the surgical group, which were the most severe ones (p=0.76). Regarding satisfaction, 12 patients (38.7%) were dissatisfied with the levonorgestrel intrauterine system and one (3.23%) was dissatisfied with the surgical treatment (p=0.00). CONCLUSION: Treatment with the levonorgestrel intrauterine system in patients with heavy menstrual bleeding and an enlarged uterus was effective, and when compared with laparoscopic hysterectomy, it had a lower rate of satisfaction and the same rate of complications, although less severe.

Transcriptomic identification of differentially expressed genes in Levonorgestrel resistant endometrial cancer cell lines.

Endometrial cancer (EC) is the most common gynecologic malignancy in the world and incidence is steadily increasing. The Levonorgestrel Intrauterine System (LNG-IUS) is an alternative conservative treatment for early-stage EC, however, Levonorgestrel (LNG) resistance occurs for 1 in 3 people. This study aimed to present potential LNG resistance mechanisms and identify differentially expressed genes (DEGs) in EC cell lines. Two LNG resistant cell lines were developed through long term culture in LNG (MFE296R and MFE319R ). Whole transcriptome sequencing was carried out on triplicate RNA samples. EdgeR v3.32.1 was used to identify differentially DEGs. Blast2go V6.0 (BioBam software) was used for functional annotation and analysis of genomic datasets. Protein interactions were investigated using the STRING database, including the identification of genes with high levels of interaction (HUB genes). Select DEGs and HUB genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Fifteen DEGs were identified according to FDR < 0.05 and logFC < 2. Protein analysis identified six HUB genes with a degree of connectivity > 10. Relative mRNA expression of MAOA, MAOB, THRSP, CD80, NDP, LINC01474, DUSP2 and CXCL8 was significantly upregulated in both LNGR cell lines. Relative protein expression of GNAO1 and MAOA were significantly upregulated in both LNGR cell lines. This research identified novel markers of resistance in LNGR cell lines. We discussed potential mechanisms of LNG resistance including dedifferentiation and immunostimulation. The next step for this research is to validate these findings further in both translational and clinical settings.

Comparing levonorgestrel intrauterine system with hysteroscopic niche resection in women with postmenstrual spotting related to a niche in the uterine cesarean scar: a randomized, open-label, controlled trial.

BACKGROUND: Postmenstrual spotting and chronic pelvic pain after cesarean delivery are associated with the presence of niches. Levonorgestrel intrauterine system (52 mg) and hysteroscopic niche resection have been shown to relieve niche-related symptoms at 6 months after the intervention. OBJECTIVE: This trial aimed to compare the effectiveness of 52-mg levonorgestrel intrauterine system with that of hysteroscopic niche resection in reducing niche-related postmenstrual spotting. STUDY DESIGN: This randomized, open-label, controlled trial was conducted at a medical center in Shanghai, China. Women with symptoms of postmenstrual spotting after cesarean delivery, with a niche depth of at least 2 mm and residual myometrium of at least 2.2 mm on magnetic resonance imaging, and no intention to conceive within the next year were randomly assigned to receive treatment with 52-mg levonorgestrel intrauterine system or hysteroscopic niche resection. The primary outcome was the reduction in postmenstrual spotting at 6 months after randomization, defined as the percentage of women with a reduction of at least 50% in spotting days relative to baseline. Efficacy and safety were assessed using intention-to-treat analysis. RESULTS: Between September 2019 and January 2022, 208 women were randomized into the levonorgestrel intrauterine system group (N=104) or the hysteroscopic niche resection group (N=104). At the 6-month follow-up, a 50% reduction in spotting had occurred in 78.4% (80/102) of women in the levonorgestrel intrauterine system group and in 73.1% (76/104) of women in the hysteroscopic niche resection group (relative risk, 1.07 [95% confidence interval, 0.92-1.25]; P=.370). Spotting decreased over time (Ptrend=.001), with a stronger reduction observed in the levonorgestrel intrauterine system group (P=.001). There was also a significant interaction between time and treatment (P=.007). From 9 months onward, a more significant reduction in spotting was observed in the levonorgestrel intrauterine system group than in the hysteroscopic niche resection group (9 months, 89.2% vs 72.1%; relative risk, 1.24 [95% confidence interval, 1.08-1.42]; 12 months, 90.2% vs 70.2%; relative risk, 1.29 [95% confidence interval, 1.12-1.48]). Moreover, compared with the hysteroscopic niche resection group, the levonorgestrel intrauterine system group had significantly fewer postmenstrual spotting days and total bleeding days from 6 months onward (all P<.001), and less pelvic pain from 3 months onward (all P<.010). No intervention-related complications were reported in any group. During follow-up, 11 (10.8%) women reported hormone-related side effects, and 2 women (2.0%) in the levonorgestrel intrauterine system group had spontaneous partial expulsion. Meanwhile, 3 unintended pregnancies were reported in the hysteroscopic niche resection group. CONCLUSION: In women with niche-related postmenstrual spotting, the levonorgestrel intrauterine system was not more effective than hysteroscopic niche resection in reducing the number of spotting days by at least 50% at 6 months. However, the levonorgestrel intrauterine system was superior in reducing spotting from 9 months onward, and it reduced the absolute number of spotting days from 6 months onward and pelvic pain from 3 months onward.