To evaluate gene expression associated with unfavorable vaginal bleeding in users of the Etonogestrel (ENG) contraceptive implant. Prospective study involving 100 women who intended to use the ENG implant. Exclusion criteria included abnormal uterine bleeding, inability to attend a 1-year follow-up, and implant removal for reasons unrelated to vaginal bleeding or loss of follow-up. We obtained endometrial biopsies before implant placement and assessed the expression of 20 selected genes. Users maintained a uterine bleeding diary for 12 months post-implant placement. For statistical analysis, we categorized women into those with or without favorable vaginal bleeding at 3 and 12 months. Women with lower CXCL1 expression had a 6.8-fold increased risk of unfavorable vaginal bleeding at 3 months (OR 6.8, 95% CI 2.21-20.79, p < 0.001), while those with higher BCL6 and BMP6 expression had 6- and 5.1-fold increased risks, respectively. By the 12-month follow-up, women with lower CXCL1 expression had a 5.37-fold increased risk of unfavorable vaginal bleeding (OR 5.37, 95% CI 1.63-17.73, p = 0.006). Women with CXCL1 expression < 0.0675, BCL6 > 0.65, and BMP6 > 3.4 had a higher likelihood of experiencing unfavorable vaginal bleeding at 3 months, and CXCL1 < 0.158 at 12 months. Users of ENG contraceptive implants with elevated BCL6 and BMP6 expression exhibited a higher risk of breakthrough bleeding at the 3-month follow-up. Conversely, reduced CXCL1 expression was associated with an elevated risk of bleeding at both the 3 and 12-month follow-ups.

OBJECTIVE: To compare the efficacy of the levonorgestrel intrauterine system (LNG-IUS) versus megestrol acetate (MA) in inducing complete regression among women with atypical endometrial hyperplasia (AEH) who declined hysterectomy.
METHODS: In this single-center, open-label randomized controlled trial, we included 148 women with AEH who declined hysterectomy. We randomized participants to receive either daily oral MA 160 mg (n=74) or apply LNG-IUS (n=74) and scheduled their follow-up by endometrial sampling at 3, 6, 9, 12, 18, and 24 months. The success rate and duration until complete regression were the primary outcomes.
RESULTS: The mean duration until complete regression was 5.52 months (95% confidence interval [CI]=4.85-6.18) for the LNG-IUS group versus 6.87 months (95% CI=6.09-7.64) for the megestrol group (log-rank test p-value=0.011). The cumulative regression rate after 12 months was 91.9% with the LNG-IUS versus 77% with MA (p=0.026). Weight gain in the MA group 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) and 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).
CONCLUSIONS: Compared to MA, the LNG-IUS was more efficacious in treating AEH in women who declined hysterectomy, especially those with moderate/severe obesity, with fewer adverse effects and less weight gain. Extending therapy to 12 months for persistent cases would improve regression rates with reasonable safety. Alternate hysteroscopic and office sampling seemed convenient for follow-up.
BACKGROUND: ClinicalTrials.gov Identifier: NCT04385667.

OBJECTIVE: To evaluate gene expression associated with vaginal bleeding in the 52-mg hormonal intrauterine device (IUD) users.
METHODS: We conducted a prospective study involving 100 women seeking to use the 52-mg hormonal IUD for contraception. We excluded women with a history or current condition of abnormal uterine bleeding and who were unable to attend a 1-year follow up. Women who expelled the device, removed it for reasons unrelated to vaginal bleeding, or were lost to follow up were discontinued. We collected endometrial biopsies immediately before IUD placement and assessed 20 selected genes using reverse transcription quantitative polymerase chain reaction. Users maintained a uterine bleeding diary for 12 months following IUD insertion. For statistical analysis, participants were categorized into groups with or without vaginal bleeding at 3 and 12 months.
RESULTS: Women with elevated CXCL9 expression had an 8.15-fold higher likelihood of experiencing vaginal bleeding at 3 months (odds ratio [OR] 8.15, 95% confidence interval [CI] 2.24-29.61, P = 0.001). At 12 months of follow up, women with increased TIMP1 expression had a 2.74-fold higher chance of experiencing vaginal bleeding (OR 2.74, 95% CI 1.08-6.95, P = 0.033). CXCL9 ≥ 1.5 and IL17A ≥ 0.68 were associated with a higher probability of vaginal bleeding at 3 months, while TIMP1 levels ≥0.943 were linked to an increased risk of bleeding at 12 months.
CONCLUSIONS: Users of the 52-mg hormonal IUD with elevated relative CXCL9 expression face an increased risk of vaginal bleeding at 3-month follow up, whereas those with heightened TIMP1 expression are more likely to experience vaginal bleeding at 12 months.

Long-acting reversible contraceptives, including hormonal levonorgestrel-releasing intrauterine systems, are the most effective methods of reversible contraception. However, unfavorable bleeding, particularly during the first months of use, is one of the most important reasons for discontinuation or avoidance. Minimizing this as early as possible would be highly beneficial. Nonsteroidal anti-inflammatory drugs inhibiting prostaglandin synthesis are known to reduce bleeding and pain at time of menses. A levonorgestrel-releasing intrauterine system has been developed with an additional reservoir containing indomethacin, designed to be released during the initial postplacement period.
This proof-of-concept study aimed to establish whether the addition of indomethacin to the currently available levonorgestrel-releasing intrauterine system (average in vivo levonorgestrel release rate of 8 μg/24 h during the first year of use) reduces the number of bleeding and spotting days during the first 90 days of use compared with the unmodified system. The dose-finding analysis included 3 doses of indomethacin-low (6.5 mg), middle (12.5 mg), and high (15.4 mg)-to determine the ideal dose of indomethacin to reduce bleeding and spotting days with minimal side-effects.
This was a multicenter, single-blinded, randomized, controlled phase II trial conducted between June 2018 and June 2019 at 6 centers in Europe. Three indomethacin dose-ranging treatment groups (low-, middle-, and high-dose indomethacin/levonorgestrel-releasing intrauterine system) were compared with the unmodified levonorgestrel-releasing intrauterine system group, with participants randomized in a 1:1:1:1 ratio. The primary outcome was the number of uterine bleeding and spotting days over a 90-day reference (treatment) period. Secondary outcomes were the number of women showing endometrial histology expected for intrauterine levonorgestrel application and the frequency of treatment-emergent adverse events. Point estimates and 2-sided 90% credible intervals were calculated for mean and median differences between treatment groups and the levonorgestrel-releasing intrauterine system without indomethacin. Point and interval estimates were determined using a Bayesian analysis.
A total of 174 healthy, premenopausal women, aged 18 to 45 years, were randomized, with 160 women eligible for the per-protocol analysis set. Fewer bleeding and spotting days were observed in the 90-day reference period for the 3 indomethacin/levonorgestrel-releasing intrauterine system dose groups than for the levonorgestrel-releasing intrauterine system without indomethacin group. The largest reduction in bleeding and spotting days was achieved with low-dose indomethacin/levonorgestrel-releasing intrauterine system, which demonstrated a point estimate difference of -32% (90% credible interval, -45% to -19%) compared with levonorgestrel-releasing intrauterine system without indomethacin. Differences for high- and middle-dose indomethacin/levonorgestrel-releasing intrauterine system groups relative to levonorgestrel-releasing intrauterine system without indomethacin were -19% and -16%, respectively. Overall, 97 women (58.1%) experienced a treatment-emergent adverse event considered related to the study drug, with similar incidence across all treatment groups including the unmodified levonorgestrel-releasing intrauterine system. These were all mild or moderate in intensity, with 6 leading to discontinuation. Endometrial biopsy findings were consistent with effects expected for the levonorgestrel-releasing intrauterine system.
All 3 doses of indomethacin substantially reduced the number of bleeding and spotting days in the first 90 days after placement of the levonorgestrel-releasing intrauterine system, thus providing proof of concept. Adding indomethacin to the levonorgestrel-releasing intrauterine system can reduce the number of bleeding and spotting days in the initial 90 days postplacement, without affecting the safety profile, and potentially improving patient acceptability and satisfaction.

OBJECTIVE: To determine the value of endometrial thickness (ET) and Doppler indices of uterine artery (UtA) as sonographic markers in predicting endometrial cancer (EC) among postmenopausal bleeding (PMB) women in low-resource settings as Vietnam.
METHODS: This cross-sectional study was conducted at the Hue University Hospital and Hue Central Hospital between June 2016 and June 2019. The study enrolled all women who complained of PMB and were followed by transvaginal Doppler ultrasound. Their definitive histopathological examination was the gold standard for comparison.
RESULTS: The UtA Doppler indices, including resistance index (RI), pulsatility index (PI), and peak systolic velocity (PSV), were significantly lower in the malignant group than in the benign group. The threshold values of the UtA, RI ≤0.73 and PI ≤1.42, were found with an area under receiver operating characteristic curve (AUC) of 0.85-0.88, and the sensitivity and specificity were 91.3% and 83.3%, respectively. Unlike PSV, the diagnostic value was the lowest, with an AUC of 0.72. ET was a good predictor for the diagnosis of EC, with an AUC of 0.89. In women with PMB, when using the cutoff value of EC more than 12.5 mm, the sensitivity and specificity were 93.8% and 77.8%, respectively. In addition, the higher the stage of EC, the lower the RI and PI and the greater the EC.
CONCLUSIONS: ET, and RI, PI, and PSV of the UtA could help in differentiating malignant from benign endometrial changes. Pulsed ultrasonic Doppler velocimetry seems to play a role in predicting the higher stages of EC. Further studies are needed to confirm these findings.

OBJECTIVE: To evaluate the efficacy of two progestins, levonorgestrel intrauterine system (LNG-IUS) and dienogest (DNG), for adenomyosis.
METHODS: This study enrolled 157 women with adenomyosis, randomized to either LNG-IUS (n = 76) or DNG (n = 81) groups as a controlled clinical trial for 72 months. Participants were classified by three different localizations of adenomyosis: diffuse, focal, and extrinsic. VAS (Visual analog scale) score, days, and amount of uterine bleeding were assessed. Uterine volume or bone mineral density (BMD) were measured by three-dimensional ultrasonography or dual-energy X-ray absorptiometry.
RESULTS: LNG-IUS and DNG comparably reduced pain scores in patients with adenomyosis. With regard to pain control, DNG offered greater efficacy than LNG-IUS in 3 months of treatment. In all types of adenomyosis, the days of bleeding after 12 months with DNG were significantly decreased compared to those with LNG-IUS. The decrease of whole uterine body was transient in any subtypes. A comparable decrease in BMD due to age-related changes in both groups was observed.
CONCLUSIONS: LNG-IUS and DNG could be useful for long-term management of adenomyosis. In terms of durations of uterine bleeding, DNG was superior to LNG-IUS for 6 years.

OBJECTIVE: Myoma is one of the most common benign tumors of uterus and one of the most common causes of vaginal bleeding in women. The purpose of the present study is to evaluate the effect of dopamine receptor agonist cabergoline on the size of myoma and the amount of bleeding in the women with myoma of the uterus.
METHODS: The study was performed as a single blind randomized clinical trial on the women with symptomatic myoma. The women were randomly assigned in 2 groups. In the case group, 0.5mg cabergoline was prescribed weekly for three months, and in the control group, nothing was prescribed and the women only had close observation for symptoms. The reduction in symptoms including pelvic pain and duration and amount of uterine bleeding, and the size of myoma, were compared between the 2 groups.
RESULTS: 51 women finished the study (26 women in the case group and 25 women in the control group). There was no significant difference between the 2 groups according to age, gravidity, parity, history of abortion, having living children, pretreatment hemoglobin, pain and amount of uterine bleeding, uterine size, and the size of myoma. After treatment, hemoglobin levels had dropped in the control group but not in the case group (p=0.004). On the other hand, pain had also decreased significantly in the case group in comparison with the control group (p=0.001). Also, the amount of menstrual bleeding (p=0.004), uterine size (p=0.001) and the size of the largest myoma (p=0.013) showed significant reduction in the case group.
CONCLUSIONS: Cabergoline can decrease the amount of bleeding and pain in the cases of myomatous uterus and can be used for the symptomatic women who want to preserve uterus for a certain period of time.

OBJECTIVE: To compare the usefulness of vaginal danazol and diphereline in the management of intra-operative bleeding during hysteroscopy.
METHODS: Randomized controlled clinical trial.
METHODS: University hospital.
METHODS: One hundred and ninety participants of reproductive age were enrolled for operative hysteroscopy. Thirty women were excluded from the study.
METHODS: One hundred and sixty participants with submucous myomas were allocated at random to receive either vaginal danazol (200mg BID, 30 days before surgery) or intramuscular diphereline (twice with a 28-day interval).
METHODS: Severity of intra-operative bleeding, clarity of the visual field, volume of media, operative time, success rate for completion of operation and postoperative complications.
RESULTS: Overall, 145 patients completed the study. In the danazol group, 78.1% of patients experienced no intra-operative uterine bleeding, and 21.9% experienced mild bleeding. In the diphereline group, 19.4% of patients experienced no intra-operative uterine bleeding, but mild, moderate and severe bleeding was observed in 31.9%, 45.8% and 2.8% of patients, respectively. The difference between the groups was significant (p<0.001). A clear visual field was reported more frequently in the danazol group compared with the diphereline group (98.6% vs 29.2%, p<0.001). The mean operative time was 10.9 min and 10.6 min in the danazol and diphereline groups, respectively (p=0.79). The mean volume of infused media was 2.0L in both groups (p=0.99). The success rate was 100% for both groups with no intra-operative complications.
CONCLUSIONS: Both vaginal danazol and diphereline were effective in controlling uterine bleeding during operative hysteroscopy. However, vaginal danazol provided a clearer visual field.

Seventy patients with stage III or IV endometriosis were randomly assigned to 2 groups after conservative surgery. Group O (n = 35) received 3 cycles of a 28-day gonadotropin-releasing hormone agonist (GnRH-a) treatment (goserelin, 3.6 mg) starting 3-5 days postoperatively. Group M (n = 35) received the same treatment starting on days 1-5 of menstruation. Groups were further subdivided according to add-back treatment. Pre- and posttreated levels of estradiol (E2 ), follicle stimulating hormone (FSH), and luteinizing hormone (LH) and visual analog scale (VAS), Kupperman menopausal index (KMI), and bone mineral density (BMD) scores were recorded. The incidence of uterine bleeding was assessed. In both groups, serum levels of E2 , FSH, and LH and VAS scores decreased significantly after treatment. Spotting was the most frequent bleeding pattern. During cycle 1, the bleeding time in group M was much longer that than that in group O (P =.001), and the bleeding rate in group M was significantly higher than that in group O (P =.024, RR = 1.185). In patients with stage III or IV endometriosis, the efficacy of GnRH-a initiated 3-5 days postoperatively was equivalent to that of GnRH-a initiated on days 1-5 of menstruation. Female patients who initiated GnRH-a treatment 3-5 days postoperatively experienced less uterine bleeding during the first cycle of treatment.