Unmet needs in abnormal uterine bleeding due to ovulatory dysfunction.

Ovulatory disorders are a common cause of abnormal uterine bleeding in women of reproductive age. The International Federation of Gynecology and Obstetrics currently offers a causal classification system for ovulatory disorders but does not provide clear management recommendations. There remains regional disparity in treatment practices, often influenced by institutional and insurance regulations as well as cultural and religious practices. A panel of experts evaluated current gaps in ovulatory disorder management guidelines and discussed potential strategies for addressing these unmet needs. Key gaps included a lack in consensus about the effectiveness of combined estrogen and progestogen versus progestogen alone, a paucity of evidence regarding the relative effectiveness of distinct hormonal molecules, a lack of data regarding optimal treatment duration, and limited guidance on optimal sequencing of treatment. Recommendations included development of a sequential treatment-line approach and development of a clinical guide addressing treatment scenarios common to all countries, which can then be adapted to local practices. It was also agreed that current guidelines do not address the unique clinical challenges of certain patient groups. The panel discussed how the complexity and variety of patient groups made the development of one single disease management algorithm unlikely; however, a simplified, decision-point hierarchy could potentially help direct therapeutic choices. Overall, the panel highlighted that greater advocacy for a tailored approach to the treatment of ovulatory disorders, including wider consideration of non-estrogen therapies, could help to improve care for people living with abnormal uterine bleeding due to ovarian dysfunction.

A 42-year-old woman with abnormal uterine bleeding-leiomyoma (AUB-L) reporting a hemoglobin of 1.6 g/dL: a case report.

BACKGROUND: Abnormal uterine bleeding, formerly known as menometrorrhagia, is estimated to occur in up to one-third of women, commonly at menarche or perimenopause. Among many other causes, abnormal uterine bleeding is known to be caused by leiomyomas, and is itself a leading cause of severe iron deficiency and iron deficiency anemia in women. Rarely, abnormal uterine bleeding can lead to critically low hemoglobin values of less than 2 g/dL. We report here a case of a woman with abnormal uterine bleeding caused by leiomyomas presenting with severely low hemoglobin. CASE PRESENTATION: We report the case of a 42-year-old Asian American woman who presented to the emergency department with chronic abnormal uterine bleeding and symptoms of anemia, including multiple syncopal episodes and abnormally pale skin but otherwise alert and oriented. Laboratory tests found a record-low hemoglobin of 1.6 g/dL and hematocrit of 6%. Transabdominal pelvic ultrasound revealed a lower uterine segment/cervical fibroid measuring 7.5 × 5 × 7.8 cm (length × depth × width). Patient was diagnosed with abnormal uterine bleeding-leiomyoma and received five units of packed red blood cells, one unit of fresh frozen plasma, Venofer infusions, tranexamic acid, and medroxyprogesterone. She was discharged from the hospital after 4 days. CONCLUSION: To date, only a handful of cases have been reported of female patient survival following severely low hemoglobin caused by abnormal uterine bleeding. This case adds to this literature, highlighting the remarkable degree of compensation that can lead to an alert, ambulatory, and oriented patient with abnormal uterine bleeding caused by leiomyoma.

Management of unscheduled bleeding on HRT: A joint guideline on behalf of the British Menopause Society, Royal College Obstetricians and Gynaecologists, British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Faculty of Sexual and Reproductive Health, Royal College of General Practitioners and Getting it Right First Time.

Unscheduled bleeding on hormone replacement therapy (HRT) can affect up to 40% of users. In parallel with the increase in HRT prescribing in the UK, there has been an associated increase in referrals to the urgent suspicion of cancer pathway for unscheduled bleeding. On behalf of the British Menopause Society (BMS) an expert review panel was established, including primary and secondary care clinicians with expertise in the management of menopause, with representatives from key related organisations, including the Royal College of Obstetricians & Gynaecologists, the British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Royal College of General Practitioners and Faculty of Sexual and Reproductive Health, and service development partners from NHS England and GIRFT (Getting it Right First Time). For each topic, a focused literature review was completed to develop evidence led recommendations, where available, which were ratified by consensus review within the panel and by guideline groups.

Curative effect of motherwort combined with ethinylestradiol-cyproterone acetate on dysfunctional uterine bleeding.

OBJECTIVE: This study aimed to investigate the curative effect of motherwort combined with ethinylestradiol-cyproterone acetate (EE/CPA) on dysfunctional uterine bleeding (DUB). METHODS: Atotal of 68 patients with DUB were divided into a single medication group (treated with EE/CPA) and a combination medication group(treated with motherwort and EE/CPA). The clinical efficacy, uterine hemodynamic parameters, sex hormone levels, coagulation index levels, blood routine test levels, and adverse reactions of patients were evaluated. RESULTS: After three months of treatment, total treatment response rate of the combination medication group was significantly higher than that of the single medication group. Decreased uterine volume, endometrial thickness and resistance index (RI), increased pulsatility index(PI), average flow rate, and uterine artery blood flow, as well asreduced follicle-stimulating hormone (FSH), luteinizing hormone (LH),estradiol (E2), progesterone (P), activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen (FIB), thrombin time(TT), platelet count (PLT), red blood cell (RBC), and hemoglobin (Hb)levels were witnessed in patients of the two groups. In thecombination medication group, there exhibited reduced uterine volume, endometrial thickness and RI, elevated PI, average flow rate, and uterine artery blood flow, reduced P, E2, FSH, LH, aPTT, PT, FIB, TT,PLT, RBC, and Hb levels in comparison to the single medication group. CONCLUSION: The combination of motherwort and EE/CPA is clinically effective in the treatment of DUB.

The contradictive findings between ultrasound, hysteroscopy and cytokines in women with nonhormonal IUDs suffering from menorrhagia: a prospective study.

PURPOSE: The objective of this study is to assess the correlation between bleeding irregularities and the accurate placement of the intrauterine device (IUD) device in the uterine cavity, determined through transvaginal ultrasonography and hysteroscopy. In addition, the study aims to examine the cytokine profile in the uterine cavity and serum of patients experiencing bleeding irregularities after the insertion of nonhormonal IUDs. METHODS: A prospective cohort study was conducted at a single tertiary medical center, wherein patients experiencing intermenstrual bleeding and spotting after the insertion of nonhormonal IUDs were enrolled. The study involved hysteroscopic and sonographic assessments of the uterine cavity and IUD placement, along with the analysis of blood and uterine cavity cytokine profiles. RESULTS: During the period between July 2019 and February 2020, a total of eight patients who experienced intermenstrual bleeding and spotting after the insertion of nonhormonal IUDs were enrolled the study. One case was excluded since a progestative device was detected by ultrasound. Out of the five cases that underwent a thorough ultrasonographic assessment, three cases (60%) showed an embedded IUD. However, these findings were excluded by the hysteroscopic evaluation. CONCLUSION: The results suggest that ultrasonographic assessment may lead to an overdiagnosis of IUD mispositioning compared to hysteroscopy. In addition, both ultrasound and hysteroscopy have limitations in diagnosing the cause of bleeding in most cases. The role of local reactive inflammatory cytokines should be further studied.

A morphological study of symptomatic uterine niche using three-dimensional models from thin-slice magnetic resonance imaging.

RESEARCH QUESTION: Is there a correlation between various morphological parameters of the uterine niche and post-menstrual spotting using three-dimensional models from thin-slice (1 mm) magnetic resonance imaging (MRI)? DESIGN: This study retrospectively identified women diagnosed with a symptomatic niche by thin-slice MRI between December 2019 and December 2021. Univariable and multivariable linear regression models assessed the correlations between morphological parameters and the duration post-menstrual spotting. Morphological differences of the niche formed by one versus two Caesarean sections were analysed by univariable and multivariable logistic analysis. RESULTS: A total of 205 women diagnosed with symptomatic niche were included in the study. The niche among most women with post-menstrual spotting was ellipsoidal, with width greater than length greater than depth, from which niche volume was estimated based on manual measurements (volume = 0.520 × length × width × depth). Manually calculated niche length (ß = 0.257, 95% confidence interval [CI] 0.040-0.473, P = 0.020) and radiomically assessed minor axis length (ß = 0.329, 95% CI 0.009-0.795, P = 0.045) both positively correlated with the duration of post-menstrual spotting, whereas the distance between the niche and external os (ß = -0.120, 95% CI -0.202 to -0.038, P = 0.004) was inversely correlated. Women with two Cesarean sections reported more days of post-menstrual spotting (8.76 ± 3.54 versus 6.68 ± 3.90 days, P < 0.001) and had increased niche length diameter (adjusted odds ratio [aOR] 1.304, 95% CI 1.190-1.429) and a smaller surface-area-to-volume ratio (aOR 0.296, 95% CI 0.129-0.680). CONCLUSIONS: Niche-associated post-menstrual spotting correlates with the length diameter of the niche and the distance between the niche and external os. Niches in women after two Caesarean sections tend to be longer in length diameter and more spherical.

Incidence of breakthrough bleeding in transgender and gender-diverse individuals on long-term testosterone.

BACKGROUND: Little is known about the maintenance of amenorrhea among transgender and gender-diverse individuals with uteri who are using long-term testosterone gender-affirming hormone therapy. Emerging data describe breakthrough bleeding among adolescents on long-term testosterone therapy and among adults who are seeking a gender-affirming hysterectomy. More studies are needed to better understand breakthrough bleeding patterns among transgender and gender-diverse individuals with uteri who are using testosterone, including the frequency, timing, and etiology of bleeding and how these patterns may differ between adults and younger populations. OBJECTIVE: The primary aim of this study was to characterize the incidence and patterns of breakthrough bleeding in a cohort of transgender and gender-diverse individuals who had been on testosterone for longer than 12 months and who had uteri in situ. Secondary aims included identifying the time to first bleed for those who experienced breakthrough bleeding and the risk factors associated with breakthrough bleeding while on testosterone therapy. STUDY DESIGN: This was an institutional review board-approved, single tertiary center, retrospective chart review of transgender and gender diverse individuals who had been on testosterone for at least 1 year. A primary survival analysis that evaluated the incidence of bleeding was combined with descriptive analyses and an evaluation of the factors associated with bleeding. RESULTS: Of the 279 patients included in the analysis, the median age of testosterone initiation was 22 years (interquartile range, 19-41), and the median follow-up time was 34 months (range, 12-278). The absolute proportion of individuals who ever experienced breakthrough bleeding on testosterone was 34% (n=96; 95% confidence interval, 29-40). Patients who experienced breakthrough bleeding initiated testosterone at a younger age (20.5 vs 22.0 years; P=.04), had lower mean serum testosterone levels (389.14 vs 512.7 ng/dL; P=.001), were more likely to have a mean testosterone level <320 ng/dL (52% vs 48%; P=.001), and had higher mean estradiol levels (62% vs 49%; P=.003). Survival analyses estimated a breakthrough bleeding incidence rate of 0.09 per year (95% confidence interval, 0.07-1.0). Although 58 people underwent a hysterectomy during the follow-up period, 64% of the cohort who maintained a uterus eventually experienced breakthrough bleeding. The median time to the initial bleeding episode was 22 months (interquartile range, 12-201) after testosterone initiation. CONCLUSION: These results suggest that a substantial fraction of transgender and gender-diverse individuals who are using testosterone will experience at least 1 episode of breakthrough bleeding even after their initial year of testosterone use. We recommend that clinicians inform all patients that breakthrough bleeding is a common occurrence even after the first year on testosterone therapy.

Evaluating resectoscopy and the levonorgestrel intrauterine system for intermenstrual bleeding associated with cesarean scar defects: A retrospective study of treatment outcomes.

AIM: To compare and evaluate the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUD) and resectoscopy remodeling procedure for intermenstrual bleeding associated with previous cesarean delivery scar defect (PCDS). METHODS: A retrospective comparative study was conducted on patients with PCDS receiving LNG-IUD (levonorgestrel 20 µg/24 h, N = 33) or resectoscopy remodeling (N = 27). Treatment outcomes were compared over 1, 6, and 12 months. Outcomes in patients with a retroverted or large uterus size, defect size, and local vascularization also were evaluated. RESULTS: At 12 months post-treatment, there were no significant differences between groups in efficacy rate; however, the reduction of intermenstrual bleeding days was higher in the LNG-IUD group than in the resectoscopy group (13.6 vs. 8.5 days, p = 0.015). Within the first year, both groups experienced a reduction in bleeding days, but the decrease was greater in the LNG-IUD group. Individuals exhibiting increased local vascularization at the defect site experienced more favorable outcomes in the LNG-IUD group than the resectoscopy group (p = 0.016), and who responded poorly tended to have a significantly larger uterus in the LNG-IUD group (p = 0.019). No significant differences were observed in treatment outcomes for patients with a retroverted uterus or large defect in either group. CONCLUSIONS: Our findings support that the LNG-IUD is as effective as resectoscopy in reducing intermenstrual bleeding days associated with PCDS and can be safely applied to patients without recent fertility aspirations. Patients with increased local vascularization observed during hysteroscopy may benefit more from LNG-IUD intervention than resectoscopy.

Effect of a single dose of a combination injectable contraceptive for treatment of bothersome uterine bleeding in contraceptive implant(s) users: A randomized double-blind placebo-controlled trial.

OBJECTIVES: This study aimed to determine the proportion of participants whose uterine bleeding/spotting was interrupted for at least 7 days during the month after they received a combined hormonal injection. We also evaluated bleeding at 21 days and 12 weeks after the injection. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled trial in 46 contraceptive implant users who presented with bothersome uterine bleeding/spotting. A single dose of a combination injectable contraceptive or placebo was administered intramuscularly at enrollment. RESULTS: The proportions of participants whose uterine bleeding/spotting was interrupted for at least 7 days the month after they received a combined hormonal injection were higher in the combination injectable contraception group than in the placebo group (87% vs 48%, p = 0.005). Participants who reported that they were bleeding free at 21 days after treatment were 52% and 35% in the combination injectable contraception group and placebo group, respectively (p = 0.24). At 12 weeks posttreatment, 17% of participants in the combination injectable contraception group and 4% in the placebo group reported cessation of bleeding with no recurrence (p = 0.34). The median days until the first bleeding interruption was shorter in the combination injectable contraception group compared with the placebo group (1 [interquartile range, 1-2] vs 8 [interquartile range, 1-28], p = 0.007). CONCLUSIONS: The combination injectable contraception interrupted bothersome uterine bleeding/spotting in contraceptive implant(s) users compared with placebo. However, this effect was limited only within the month when the treatment was administered. IMPLICATIONS: Bothersome uterine bleeding/spotting is a common side effect leading to contraceptive implant(s) discontinuation. In implant users experiencing these symptoms with no estrogen contraindications, a combined injectable contraception appears to rapidly improve bleeding for the duration of injectable exposure (1 month).

Dysmenorrhea, intermenstrual bleeding, menstrual flow volume changes, and irregularities following COVID-19 vaccination and the association with vaccine skepticism: A retrospective observational study.

BACKGROUND: COVID-19 vaccines have provided fertile ground for research, especially with the unprecedented spread of misinformation about this disease and its vaccines. Among women, one of the most frequently reported side effects of the vaccine has been menstrual disturbance. OBJECTIVE: To investigate the perceived impact of COVID-19 vaccines on the menstrual cycle. In addition, the research seeks to identify factors that could predispose certain individuals to experience these effects, thereby contributing to a deeper understanding of the interplay between vaccines and menstrual health. DESIGN: We conducted a retrospective observational cross-sectional study. METHODS: Any woman of menstruating age who received at least one dose of the COVID-19 vaccine and currently resides in Saudi Arabia was invited to complete an online questionnaire. The questionnaire compared menstruation characteristics-regularity, volume, intermenstrual bleeding, and dysmenorrhea-before and after receiving the COVID-19 vaccine, taking into consideration possible predisposing factors such as polycystic ovarian syndrome, contraceptives, or period-blocking pills. RESULTS: Women without polycystic ovarian syndrome experienced less change in dysmenorrhea post-vaccine compared to those with polycystic ovarian syndrome (23.88% versus 37.78%, p = 0.045). Women using hormonal contraceptives were about two times more likely to experience changes in volume compared to those not using contraceptives (odds ratio = 2.09, 95% confidence interval = 1.23-3.57, p = 0.006). COVID-19 vaccine skeptics were about three times more likely to perceive changes in regularity post-vaccine compared to non-skeptics (odds ratio = 2.96, 95% confidence interval = 1.79-4.90, p < 0.001). They were also three times more likely to perceive changes in volume post-vaccine (odds ratio = 3.04, 95% confidence interval = 1.95-4.74, p < 0.001). CONCLUSION: Our data suggest significant associations between COVID-19 skepticism, the use of hormonal contraceptives, and the reported post-vaccine menstrual disturbances. This underscores the importance of public education efforts aimed at dispelling misinformation and addressing controversies related to these vaccines.

Immune Checkpoints in Recurrent Pregnancy Loss: New Insights into a Detrimental and Elusive Disorder.

Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history.

[Surgical Thrombectomy for Acute Massive Pulmonary Thromboembolism Induced by Giant Adenomyosis Uteri:Report of a Case].

A 52-year-old woman had giant adenomyosis uteri treated by pseudo-menopause therapy. However, she did not take oral anticoagulant for deep vein thrombosis prevention because of metrorrhagia. She developed pulmonary thromboembolism, and was refered to our department. She complained mild dyspnea but free from leg edema. Enhanced computed tomography (CT) showed massive thrombi in the central pulmonary artery trunk. Therefore, she underwent emergency thrombectomy. Three days later, uterine artery embolization( UAE) was performed to control metrorrhagia worsened by anticoagulation therapy. However, UAE caused significant swelling of the uterus, and bi-lateral external iliac veins were more compressed. Two months later, total hysterectomy was performed to prevent recurrence of pulmonary thromboembolism( PTE). Clinical course thereafter was satisfactory.

Retrospective Study of First Trimester Metrorrhagia: Pregnancy Follow-Up and Relationship with the Appearance of Gestational Complications.

Background and Objectives: The purpose of this study was to describe and evaluate the bleeding that occurs during the first weeks of gestation and its implications throughout pregnancy. Secondarily, we assessed the associated complications in order to identify potential risk factors that could be used to select women at higher risk of adverse outcomes that could benefit from an early diagnosis and improved monitoring. Materials and Methods: We made a selection of all the women who consulted in the Emergency Department of the Hospital QuirónSalud in Malaga on 2015 presenting with first trimester metrorrhagia. We refer to first trimester metrorrhagia as that which occurs until week 12 + 6. Once these pregnant women were identified, we studied several variables not related to the gestation and some others associated with it and its natural course. Results: The average age of the patients assessed was 34.1. Associated gestational complications were metrorrhagia in the second trimester (6.3%), threatened preterm labor (7.4%), preeclampsia (2.5%), gestational diabetes (7.4%), late abortion (1.2%), and early postpartum hemorrhage (1.8%). We sought associations to assess possible risk factors, establishing an increased maternal age as an aggravating factor for the development of complications. We also studied gestational complications, finding a higher prevalence of them in older women, such as prematurity (33.11 vs. 34.48 years), gestational diabetes (33.11 vs. 36.06 years), and preeclampsia (33.25 vs. 35 years). Conclusions: Maternal age is a risk factor for first-trimester spontaneous miscarriage and for the development of complications of pregnancy. It is crucial to perform a correct screening of different pathologies throughout the pregnancy to anticipate potential complications.

Study protocol for assessment of the coagulation potential of concomitantly used factor VIII concentrates in patients with haemophilia A with emicizumab prophylaxis (CAGUYAMA Study): a multicentre open-label non-randomised clinical trial.

INTRODUCTION: Emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (HA). The haemostatic efficacy of emicizumab in patients with HA is estimated as approximately 15% based on mimic activity of factor (F) VIII. Although it has been proven effective in preventing bleeding, its haemostatic effect during breakthrough bleeding or surgery is considered insufficient. Therefore, haemostatic management of emicizumab-treated patients with HA without inhibitors frequently requires FVIII replacement therapy. In haemostatic management of emicizumab-treated patients with HA, conventional FVIII dosage calculations are used in clinical practice without considering the coagulant effects of emicizumab. METHODS AND ANALYSIS: In the CAGUYAMA study, 100 patients with HA without inhibitors will be enrolled for a maximum duration of 1 year, and samples of 30 events following the concomitant use of FVIII concentrates (30±5 U/kg) with emicizumab will be collected. An 'event' is defined as obtaining blood samples at preadministration and postadministration of FVIII concentrates during a breakthrough bleeding or a surgical procedure. Global coagulation assays will be used to measure the coagulation potential of the obtained samples. Clot waveform analysis (CWA) is used to identify the primary end-point, that is, the degree of improvement in the maximum coagulation rate at preadministration and post-administration of fixed-dose FVIII concentrations. The parameter obtained from CWA, which is triggered by an optimally diluted mixture of prothrombin time reagent and activated partial thromboplastin time reagent, is reported to be an excellent marker for assessing the degree of improvement of the coagulation potential in emicizumab-treated plasmas. ETHICS AND DISSEMINATION: The CAGUYAMA study was approved by the Japan-Certified Review Board of Nara Medical University (Approval ID; nara0031). The study results will be communicated through publication in international scientific journals and presentations at (inter)national conferences. TRIAL REGISTRATION NUMBER: jRCTs051210137.

Assessment of the clinical outcomes and complications of hysteroscopic and laparoscopic approaches in the treatment of symptomatic isthmocele: An observational study.

OBJECTIVES: To investigate the outcomes of patients undergoing laparoscopic or hysteroscopic approaches for isthmoplasty. METHODS: A total of 99 isthmocele patients with an average age of 38.45 ± 4.72 years were included in the 2 years of this retrospective cohort study. Forty-five underwent laparoscopic and 54 underwent hysteroscopic isthmocele excision and myometrial repair. RESULTS: Pain scores were significantly higher in the hysteroscopy group before the procedure, but there were no significant pain score differences after the surgery. In 1 year of follow up, dysmenorrhea and dyspareunia were higher among hysteroscopy patients. Furthermore, hysteroscopy significantly improved postmenstrual spotting after surgery better than laparoscopy, but in the follow up, there was no significant difference between the two groups in this regard (mean rank for hysteroscopy vs. laparoscopy: 32.30 vs. 37.48, U = 418, P = 0.29). CONCLUSION: In patients with a history of infertility, ectopic pregnancy, lower gravidity, lower parity, and a lower number of cesarean sections, laparoscopic isthmoplasty is preferred over the hysteroscopic approach. Both methods have similar effects on midcycle vaginal bleeding, duration of postmenstrual spotting, and pain. However, a higher rate of dyspareunia and dysmenorrhea could be associated with hysteroscopy.

The association between uterine scar defect (niche) and the presence of symptoms.

RESEARCH QUESTION: Is there association between the presence of a uterine niche and the presence of symptoms? DESIGN: This cross-sectional study was conducted at a single tertiary medical centre. All women who underwent Caesarean section from January 2017 to June 2020 were invited to the gynaecological clinics, and requested to complete a questionnaire regarding symptoms related to the presence of a niche (heavy menstrual bleeding, intermenstrual spotting, pelvic pain, infertility). Transvaginal two-dimensional ultrasonography was performed to assess the uterus and uterine scar characteristics. The primary outcome was defined as the presence of a uterine niche, evaluated by length, depth, residual myometrial thickness (RMT) and ratio between the residual myometrial thickness (RMT) and adjacent myometrial thickness (AMT). RESULTS: Of 524 women who were eligible and scheduled for evaluation, 282 (54%) completed the follow-up; 173 (61.3%) were symptomatic and 109 (38.6%) asymptomatic. Niche measurements, including RMT/AMT ratio, were comparable between the groups. In a sub-analysis of each symptom, heavy menstrual bleeding and intermenstrual spotting were associated with reduced RMT (P = 0.02 and P = 0.04, respectively) compared with women with normal menstrual bleeding. An RMT less than 2.5 mm was significantly more prevalent in women reporting heavy menstrual bleeding (11 [25.6%] versus 27 [11.3%]; P = 0.01] and new infertility (7 [16.3%] versus 6 [2.5%]; P = 0.001]. In logistic regression analysis, infertility was the only symptom associated with an RMT less than 2.5 mm (B = 1.9; P = 0.002). CONCLUSIONS: A reduced RMT was found to be associated with heavy menstrual bleeding and intermenstrual spotting, while values below 2.5 mm were also associated with infertility.

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.

Angiogenesis in abnormal uterine bleeding: a narrative review.

BACKGROUND: Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation. OBJECTIVE AND RATIONALE: We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms. SEARCH METHODS: A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale. OUTCOMES: Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures. WIDER IMPLICATIONS: AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more fragile and permeable vessels. This matches our hypothesis and these mechanisms appear to play an important role in the pathophysiology of AUB-E and AUB-I. Exploring the alterations in angiogenesis in these patients could provide treatment targets for AUB.