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.

Treatments of unscheduled vaginal bleeding due to progestin-only contraception.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness, safety, and side effects associated with the usage of different treatments for unscheduled vaginal bleeding in premenopausal women using progestin-only pills.

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.

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.

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.

Safety of FEIBA and emicizumab (SAFE): Dose escalation study evaluating the safety of in vivo administration of activated prothrombin complex concentrate in haemophilia A patients on emicizumab.

INTRODUCTION: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A. Breakthrough bleeding still occurs in patients on emicizumab and can be managed with recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC). Thrombotic events were reported when patients on emicizumab received concomitant aPCC at relatively high doses. We studied the effect of infusing various doses of aPCC to patients on emicizumab. MATERIAL AND METHODS: Nine patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Patients were infused with varying doses of aPCC in vivo. Samples were tested with thrombin generation (TG) assay. RESULTS: In the current in vivo arm of the study four out of nine patients reached the highest dose, 75 U/kg of aPCC and six out of nine patients were actually eligible for the highest dose. In the previous in vitro arm of the study seven out of eight patients reached the normal plasma with spiking aPCC at a very low concentration equivalent to 5 U/kg. CONCLUSION: The in vitro portion of the study demonstrated that clinically relevant concentrations of aPCC resulted in excessive TG, however, in vivo administration of aPCC to the same patients demonstrated that most of the patients had normal TG at the approved doses of aPCC. In the management of breakthrough bleeding clinicians should heed the boxed warning for concomitant use of emicizumab and aPCC, however, should also be aware that low doses of aPCC may not result in sufficient TG.

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.

The effect of a combined indomethacin and levonorgestrel-releasing intrauterine system on short-term postplacement bleeding profile: a randomized proof-of-concept trial.

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

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.