Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Association of heavy menstrual bleeding with cardiovascular disease in US female hospitalizations.

BACKGROUND: Heavy menstrual bleeding (HMB) is a common menstrual disorder associated with multiple risk factors of cardiovascular disease (CVD) in women. In addition, HMB is often present with irregular menstruation (IM) which is a risk factor for CVD outcomes. However, the relationship between HMB and CVD outcomes is unexplored in the presence or absence of IM. We determined the association of HMB with multiple CVD outcomes using a nationally representative sample of female hospitalizations in the US. METHODS: All hospitalizations of females with HMB diagnosis and normal menstrual cycles from ages of 18 to 70 years were extracted from the National Inpatient Sample Database, 2017. The HMB was defined using the International Classification of Diseases (ICD)-10 for excessive and frequent menstruation bleeding and included any current or history of HMB diagnosis. Outcomes including major adverse cardiovascular events (MACE), coronary heart disease (CHD), stroke, heart failure (HF), atrial fibrillation (AF) or arrhythmia, myocardial infarction (MI), and diabetes (DM) were defined using ICD-10 codes. Adjusted logistic regression and prosperity scores-matched logistic regression analyses were conducted to summarize adjusted associations with an odds ratio (OR) and a 95% confidence interval (CI). RESULTS: Among 2,430,851 hospitalizations, HMB was observed in 7762 (0.68%) females with age ≤ 40 years and 11,164 (0.86%) females with age > 40 years. Among hospitalizations with age ≤ 40 years, HMB was significantly associated with increased odds of CVD outcomes including MACE (OR = 1.61; 95% CI: 1.25, 2.08), CHD (OR = 1.72; 95% CI: 1.10, 2.71), stroke (OR = 1.95; 95% CI: 1.12, 3.40), HF (OR = 1.53; 95% CI: 1.15, 2.03), and AF/arrhythmia (OR = 1.84; 95% CI: 1.34, 2.54). These associations were confirmed in multiple sensitivity analyses. In contrast, HMB was not robustly associated with CVD events among hospitalizations of women with age > 40 years. HMB without IM was strongly associated with DM, HF, AF, and MACE outcomes while HMB with IM was strongly associated with CHD and AF outcomes in hospitalizations of young women. CONCLUSIONS: HMB is associated with CVD events among US hospitalizations of young women. A routine investigation and screening of menstrual disorders, especially HMB, is useful for CVD risk stratification and management in young women.

A rare case of glanzmann thrombasthenia with concomitant factor VII deficiency.

Glanzmann thrombasthenia and clotting factor VII deficiency are rare autosomal recessive bleeding disorders. But the occurrence of both in the same person is an extremely rare phenomenon. Here, we present the case of a young female from Sindh, Pakistan that got diagnosed with Glanzmann thrombasthenia and concomitant moderate factor VII deficiency, a combination not previously reported in the country. The patient exhibited typical clinical manifestations including menorrhagia, nasal bleeds, and prolonged bleeding after minor injuries, compounded by a positive family history and consanguinity. Laboratory investigations revealed marked anemia, prolonged bleeding time, and abnormal platelet aggregation studies consistent with Glanzmann thrombasthenia. The identification of this rare combination relied on comprehensive clinical evaluation, emphasizing the importance of family history in suspected cases. Management involved platelet transfusions, tranexamic acid, and Factor VII replacement, resulting in clinical improvement.

Assessment of rare bleeding disorders in adolescents with heavy menstrual bleeding.

INTRODUCTION: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. AIM: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. METHODS: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. RESULTS: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. CONCLUSION: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

Driving improvement of diagnosis and awareness of heavy menstrual bleeding in women among physicians.

INTRODUCTION: A number of barriers in care exist for women/girls with bleeding disorders. Little progress has been made to overcome them, particularly regarding levels of awareness of healthcare professionals (HCPs) and women/girls. AIM: To evaluate awareness and perception of heavy menstrual bleeding (HMB) and bleeding disorders among HCPs and women/girls. METHODS: A three-part qualitative study was conducted, including HCPs and women/girls from over seven countries. Part 1 included eleven 60-min interviews with experts discussing HMB diagnostic barriers, which were further assessed in surveys among 6099 women/girls, 353 general practitioners (GPs), and 426 obstetricians and gynaecologists (OB/GYNs) during Part 2. Part 3 included three 1.5-2-h workshops with 20 clinicians and patient representatives covering HMB knowledge, criteria defining HMB and HCP resourcing for diagnosis. RESULTS: Many HCPs do not conduct certain investigations for women/girls presenting with HMB, and 22% of GPs lack confidence in the management of HMB. Only 8% of GPs use screening tools to evaluate menstrual blood loss, and 13% of GPs and 15% of OB/GYNs assess underlying bleeding disorders. Seventy-six percent of menstruating women/girls believed they could recognise HMB symptoms 'well'. However, 23% of these women/girls would not seek medical advice for abnormal/prolonged menstruation disrupting their lives. Disruptions were reported in 34% of women/girls from the general population and 61% of women with at-risk symptoms of HMB. CONCLUSION: Many women/girls and HCPs have limited awareness of important HMB indicators. There is a need for standardized clinical criteria to promote efficient diagnoses and management.

Women and girls with inherited bleeding disorders: Focus on haemophilia carriers and heavy menstrual bleeding.

Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management.

Adenomyosis diagnosis among adolescents and young women with dysmenorrhoea and heavy menstrual bleeding.

RESEARCH QUESTION: What is the prevalence of adenomyosis at ultrasonography among adolescents and young women reporting dysmenorrhoea and/or heavy menstrual bleeding (HMB)? DESIGN: This observational cohort study involved adolescents and young women referred for dysmenorrhoea and/or HMB to the Adolescent Medicine Unit at Careggi University Hospital, Italy. Patients with endometriosis and bleeding disorders were excluded. Transvaginal ultrasonography or transrectal sonography using a transvaginal probe was performed. The myometrium was described according to the Morphological Uterus Sonographic Assessment criteria. Details of baseline characteristics, clinical data and symptoms were collected. The presence of sonographic features of adenomyosis and the association between imaging findings and clinical symptoms were evaluated. RESULTS: The cohort included 95 patients aged between 13 and 25 years, referred for dysmenorrhoea (88.4%), HMB (23.2%) or both (13.7%). According to the MUSA criteria the sonographic diagnosis of adenomyosis was made in 27.4% of patients, with the diffuse type the most prevalent. Uterine wall asymmetry, hyperechoic intramyometrial islands, translesional vascularity and an interrupted junctional zone were the most common features. Patients with imaging findings of adenomyosis had significantly higher rates of HMB than those with a normal myometrial appearance (38.5% versus 17.4%, P = 0.030). In addition, the coexistence of dysmenorrhoea and HMB was significantly associated with adenomyosis (odds ratio 5.68, 95% confidence interval 1.65-19.5). CONCLUSIONS: Adenomyosis may be diagnosed among teenagers and young women referred with dysmenorrhoea and/or HMB. The clinical presentation is relevant for the diagnosis, with HMB alone and HMB plus dysmenorrhoea significantly associated with the sonographic identification of adenomyosis.

Relugolix combination therapy in Black/African American women with symptomatic uterine fibroids: LIBERTY Long-Term Extension study.

BACKGROUND: In the LIBERTY Long-Term Extension study, once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) substantially improved uterine fibroid-associated heavy menstrual bleeding throughout the 52-week treatment period in the overall study population. OBJECTIVE: Black or African American women typically experience a greater extent of disease and symptom burden of uterine fibroids vs other racial groups and have traditionally been underrepresented in clinical trials. This secondary analysis aimed to assess the efficacy and safety of relugolix combination therapy in the subgroup population of Black or African American women with uterine fibroids in the LIBERTY Long-Term Extension study. STUDY DESIGN: Black or African American premenopausal women (aged 18-50 years) with uterine fibroids and heavy menstrual bleeding who completed the 24-week randomized, placebo-controlled, double-blind LIBERTY 1 (identifier: NCT03049735) or LIBERTY 2 (identifier: NCT03103087) trials were eligible to enroll in the 28-week LIBERTY Long-Term Extension study (identifier: NCT03412890), in which all women received once-daily, open-label relugolix combination therapy. The primary endpoint of this subanalysis was the proportion of Black or African American treatment responders: women who achieved a menstrual blood loss volume of <80 mL and at least a 50% reduction in menstrual blood loss volume from the pivotal study baseline to the last 35 days of treatment by pivotal study randomized treatment group. The secondary outcomes included rates of amenorrhea and changes in symptom burden and quality of life. RESULTS: Overall, 241 of 477 women (50.5%) enrolled in the LIBERTY Long-Term Extension study self-identified as Black or African American. In Black or African American women receiving continuous relugolix combination therapy for up to 52 weeks, 58 of 70 women (82.9%; 95% confidence interval, 72.0%-90.8%) met the treatment responder criteria for reduction in heavy menstrual bleeding (primary endpoint). A substantial reduction in menstrual blood loss volume from the pivotal study baseline to week 52 was demonstrated (least squares mean percentage change: 85.0%); 64.3% of women achieved amenorrhea; 59.1% of women with anemia at the pivotal study baseline achieved a substantial improvement (>2 g/dL) in hemoglobin levels; and decreased symptom severity and distress because of uterine fibroid-associated symptoms and improvements in health-related quality of life through 52 weeks were demonstrated. The most frequently reported adverse events during the cumulative 52-week treatment period were hot flush (12.9%), headache (5.7%), and hypertension (5.7%). Bone mineral density was preserved through 52 weeks. CONCLUSION: Once-daily relugolix combination therapy improved uterine fibroid-associated heavy menstrual bleeding in most Black or African American women who participated in the LIBERTY Long-Term Extension study. The safety and efficacy profile of relugolix combination therapy in Black or African American women was consistent with previously published results from the overall study population through 52 weeks. Findings from this subanalysis will assist shared decision-making by helping providers and Black or African American women understand the efficacy and safety of relugolix combination therapy as a pharmacologic option for the management of uterine fibroid-associated symptoms.

A 52-mg levonorgestrel-releasing intrauterine system vs bipolar radiofrequency nonresectoscopic endometrial ablation in women with heavy menstrual bleeding: long-term follow-up of a multicenter randomized controlled trial.

BACKGROUND: The symptom of heavy menstrual bleeding has a substantial impact on professional, physical, and social functioning. In 2021, results from a randomized controlled trial comparing a 52-mg levonorgestrel-releasing intrauterine system and radiofrequency nonresectoscopic endometrial ablation as treatments for women with heavy menstrual bleeding were published. Both treatment strategies were equally effective in treating heavy menstrual bleeding during 2-year follow-up. However, long-term results are also relevant for both patients and healthcare providers. OBJECTIVE: This study aimed to assess long-term differences in reintervention risk and menstrual blood loss in women with the symptom of heavy menstrual bleeding treated according to a strategy starting with a 52-mg levonorgestrel-releasing intrauterine system or radiofrequency nonresectoscopic endometrial ablation. STUDY DESIGN: This study was a long-term follow-up study of a multicenter randomized controlled trial (MIRA trial), in which women were allocated to either a 52-mg levonorgestrel-releasing intrauterine device (n=132) or radiofrequency nonresectoscopic endometrial ablation (n=138). Women from the original trial were contacted to fill out 6 questionnaires. The primary outcome was the reintervention rate after allocated treatment. Secondary outcomes included surgical reintervention rate, menstrual bleeding measured by the Pictorial Blood Loss Assessment Chart, (disease-specific) quality of life, sexual function, and patient satisfaction. RESULTS: From the 270 women who were randomized in the original trial, 196 (52-mg levonorgestrel-releasing intrauterine system group: n=94; radiofrequency nonresectoscopic endometrial ablation group: n=102) participated in this long-term follow-up study. Mean follow-up duration was 7.4 years (range, 6-9 years). The cumulative reintervention rate (including both medical and surgical reinterventions) was 40.0% (34/85) in the 52-mg levonorgestrel-releasing intrauterine system group and 28.7% (27/94) in the radiofrequency nonresectoscopic endometrial ablation group (relative risk, 1.39; 95% confidence interval, 0.92-2.10). The cumulative rate of surgical reinterventions only was significantly higher among patients with a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system compared with radiofrequency nonresectoscopic endometrial ablation (35.3% [30/85] vs 19.1% [18/94]; relative risk, 1.84; 95% confidence interval, 1.11-3.10). However, the hysterectomy rate was similar (11.8% [10/94] in the 52-mg levonorgestrel-releasing intrauterine system group and 18.1% [17/102] in the radiofrequency nonresectoscopic endometrial ablation group; relative risk, 0.65; 95% confidence interval, 0.32-1.34). Most reinterventions occurred during the first 24 months of follow-up. A total of 171 Pictorial Blood Loss Assessment Chart scores showed a median bleeding score of 0.0. No clinically relevant differences were found regarding quality of life, sexual function, and patient satisfaction. CONCLUSION: The overall risk of reintervention after long-term follow-up was not different between women treated according to a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system and those treated using a strategy starting with radiofrequency nonresectoscopic endometrial ablation. However, women allocated to a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system had a higher risk of surgical reintervention, which was driven by an increase in subsequent endometrial ablation. Both treatment strategies were effective in lowering menstrual blood loss over the long term. The results of this long-term follow-up study can support physicians in optimizing the counseling of women with heavy menstrual bleeding, thus promoting informed decision-making regarding choice of treatment.

Meclizine improves endometrial repair and reduces simulated menstrual bleeding in mice with induced adenomyosis.

BACKGROUND: Adenomyosis is one of the structural causes of abnormal uterine bleeding, which often presents as heavy menstrual bleeding. Mostly because of the poor understanding of its pathophysiology, medical management of adenomyosis-induced heavy menstrual bleeding is still a challenge. We have previously reported that glycolysis is crucial to endometrial repair following menstruation and that suppressed glycolysis can cause heavy menstrual bleeding. OBJECTIVE: This study aimed to test the hypothesis that meclizine, a drug with an excellent safety profile, alleviates heavy menstrual bleeding in mice with induced adenomyosis using a simulated menstruation model. STUDY DESIGN: Adenomyosis was induced in 36 female C57BL/6 mice using endometrial-myometrial interface disruption. Three months after induction, the mice were randomly divided into the following 3 groups: low-dose meclizine, high-dose meclizine, and controls. Treatment with meclizine or vehicle started shortly before the simulated menstruation procedure and ended before progesterone withdrawal. The amount of blood loss was quantified and uterine tissue was harvested for histologic evaluation of the grade of endometrial repair. We performed immunohistochemistry analysis of 4 proteins critically involved in glycolysis: Glut1 (glucose transporter 1), Hk2 (hexokinase 2), Pfkfb3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3), and Pkm2 (pyruvate kinase M2). The extent of tissue fibrosis in both ectopic and eutopic endometria was evaluated using Masson trichrome staining. RESULTS: In mice with induced adenomyosis, meclizine accelerated endometrial repair in a dose-dependent manner and reduced the amount of menstrual bleeding. Meclizine administration raised endometrial immunoexpression of Hk2 and Pfkfb3 but not of Glut1 or Pkm2. The extent of endometrial fibrosis was reduced following the meclizine administration. Remarkably, these favorable changes were accompanied by the suppression of lesional progression, as evidenced by the dose-dependent reduction in the extent of fibrosis (a surrogate for lesional progression). CONCLUSION: These encouraging results, taken together, suggest that glycolysis may be a promising therapeutic target and that meclizine may hold therapeutic potential as a nonhormonal treatment for adenomyosis-induced heavy menstrual bleeding without exacerbating the disease.

Adequate menstrual suppression in adolescents with inherited bleeding disorders often requires multiple treatment changes: Retrospective cohort study of a multidisciplinary clinic.

Heavy menstrual bleeding (HMB) is often the presenting symptom for females with inherited bleeding disorders (IBD). Multidisciplinary clinics leverage the expertise of hematologists and women's health specialists. This study characterizes the complexity of HMB management for adolescents with IBDs from a large multidisciplinary clinic. Adolescents often required multiple different menstrual suppression treatments, with only about 20% achieving acceptable suppression with their first treatment. Adolescents switched therapy most often for uncontrolled bleeding, followed by adverse effects, and patient preference. Given the difficulty in achieving adequate menstrual suppression, multidisciplinary clinics offer necessary expertise in accomplishing bleeding control with minimal adverse effects.

Standardizing the evaluation and management of iron deficiency anemia secondary to heavy menstrual bleeding in the emergency department.

BACKGROUND: Comprehensive guidelines for the management of iron deficiency anemia (IDA) in adolescents with heavy menstrual bleeding (HMB) presenting to the emergency department (ED) are lacking, leading to variability in care. We aimed to standardize the evaluation and management of these patients through the development and implementation of an evidence-based algorithm using quality improvement methodology. METHODS: Baseline data of the target population identified variability across four key measures of clinical management: therapy choice and administration, laboratory evaluation, hematology service consultation, and patient disposition. Literature review and consensus from pediatric hematology and gynecology providers informed a draft algorithm that was refined in an iterative multidisciplinary process. From December 2022 to July 2023, we aimed to achieve a 25% relative increase in patients to receive optimal management per the algorithm, while using sequential Plan-Do-Study-Act (PDSA) cycles. Process measures focusing on provider documentation and balancing measures, such as ED length of stay, were assessed concurrently. RESULTS: Forty-nine patients were evaluated during four PDSA cycles. Improvement of ≥40% above baseline regarding recommended therapy administration was achieved across four PDSA cycles. Adherence to recommended therapy choice improved from 57% (baseline) to 100%, minimal laboratory evaluation from 14% to 83%, hematology consultation from 36% to 100%, and appropriate disposition from 71% to 100%. ED length of stay remained stable. CONCLUSION: Implementation of a standardized algorithm for management of IDA secondary to HMB in adolescents in the ED increased adherence to evidence-based patient care.

Real-world experience of direct oral anticoagulant use in a single pediatric center.

BACKGROUND: Pediatric venous thromboembolism has increased by 130%-200%, specifically in hospitalized children, and direct oral anticoagulants (DOACs) offer several therapeutic advantages. METHODS: This study aims to evaluate the real-world epidemiological and outcome data from a retrospective review of pediatric patients treated with DOACs from January 1, 2013 to December 31, 2022. In this single-center, IRB-approved study, 65 patients were identified and analyzed using SPSS statistical software, and a descriptive statistical analysis was conducted. RESULTS: Of the 65 patients, 37% were on apixaban, 61.5% were on rivaroxaban, and 1.5% were on dabigatran. Per the 2023 ISTH outcome definitions, one (2%) patient had a major bleeding episode, six (9%) had clinically relevant non-major bleeding, three (5%) patients had patient-important heavy menstrual bleeding (HMB), and one (1.5%) patient had minor bleeding. Seven (19%) of 37 postmenarchal patients had evidence of HMB. Six (9.2%) patients had recurrent venous thromboembolism while on a DOAC (one was on apixaban, and five were on rivaroxaban) and were transitioned to other forms of anticoagulation. CONCLUSION: Thus, bleeding rates after DOAC therapy are comparable to previous DOAC trials, as well as other anticoagulants in pediatrics. HMB is an important outcome measure and should continue to be investigated. This study reports a higher rate of recurrent thrombosis (9.2%) compared to other trials. However, this observation may be attributed to patients who had ongoing risk factors, as well as a longer duration of study follow-up. Additional multicentered outcome studies evaluating DOAC use in children are needed to determine long-term recurrence and HMB risks.

Gynecological bleeding in women with congenital bleeding disorders: A comprehensive cohort from Iran.

BACKGROUND: Gynecological bleeding including menorrhagia and postpartum hemorrhage (PPH) face women's quality of life constantly with difficulties, especially those suffering from inherited bleeding disorders. In this study, we aim to evaluate gynecological bleeding particularly menorrhagia among Iranian women patients with inherited bleeding disorders admitted to the Iranian Comprehensive Hemophilia Care Center (ICHCC). METHODS: This study was conducted on 156 females aged ≥ 12 diagnosed with an inherited bleeding disorder in ICHCC. Demographic and laboratory data were documented for all patients. Bleeding questionnaires (the International Society on Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT), Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease (MCMDM-1), and Pictorial blood loss assessment chart (PBAC)) were filled out for all patients. For comparing metric and categorical parameters, Mann-Whitney was performed. Spearman's rho test was used for analyzing correlation. RESULTS: The mean age of patients was 33. Von Willebrand disease (VWD), Factor (F) VII deficiency and combined factor deficiency were the most diagnosed disorders. The median of ISTH-BAT, MCMDM-1, and PBAC was 7,7, and 517, respectively. Menorrhagia was the most common reason for diagnosis. Menorrhagia and PPH domain scores ≥ 2 were recorded in 82 and 34 patients, respectively, and PBAC scores > 100 were seen in 118 patients. Significant positive correlations were observed between bleeding scores and menorrhagia and PPH scores. No significant correlations were recorded for VWF: Ag and VWF: RCo with menorrhagia and PPH scores; however, significant correlations were seen for VWF: Ag and VWF: RCo with bleeding score questionnaires. CONCLUSION: Menorrhagia is the most common problem in females affected by different types of inherited bleeding disorders, particularly VWD. Increased awareness among gynecologists and hematologists about bleeding disorders in cases with unexplained menorrhagia is an essential step for optimal management.

Menstrual blood loss is an independent determinant of hemoglobin and ferritin levels in premenopausal blood donors.

INTRODUCTION: To prevent blood donors from developing iron deficiency (ferritin <15 µg/L) and subsequent anemia (hemoglobin <120 g/L), blood services rely on information about known risk factors, including the donor's sex and age. For example, while Finnish women are able to donate whole blood with a minimum donation interval of 91 days, women in the 18 to 25-year-old age group are recommended to donate no more than once per year. Menstrual blood loss is not accounted for in blood donation interval recommendations, despite being a known risk factor of iron deficiency. We aim to investigate to what extent menstrual bleeding is associated with ferritin and hemoglobin levels in female blood donors, and quantify the association of other menstruation-related variables not currently accounted for by blood services (i.e., use of hormonal contraception, heavy menstrual bleeding) with iron deficiency or anemia. MATERIAL AND METHODS: The study population consisted of 473 premenopausal and 491 postmenopausal Dutch whole blood donors. Exclusion criteria were current pregnancy, BMI ≥50, ferritin ≥200, pictorial blood assessment chart (PBAC) ≥400, and age <18 or ≥70 years. Menstrual blood loss was quantified using a PBAC, a semiquantitative method to evaluate the number of used menstrual products and the degree of staining. We identified predictors of log(ferritin)/hemoglobin and iron deficiency/anemia using Bayesian linear and logistic regression models and quantified the average percentage of variance in log(ferritin) and hemoglobin explained by the covariates. RESULTS: Menstrual blood loss accounted for most of the explained variance in hemoglobin (8%) and second only to the number of days since last donation for ferritin (8%). Heavy menstrual bleeding (PBAC ≥150, OR = 3.56 [1.45-8.85], prevalence 13%) was associated with anemia, and use of levonorgestrel-releasing intrauterine device was negatively associated with iron deficiency (OR = 0.06 [0.01-0.44]). After statistical control for menstrual blood loss, age was not associated with iron status. CONCLUSIONS: Menstrual blood loss and blood donation were the most important determinants of iron status in premenopausal women. Thus, results suggest that accounting for menstrual blood loss in donation interval guidelines may benefit blood donors.

Patients' motives and considerations on treatment decision-making for heavy menstrual bleeding: a qualitative study.

BACKGROUND: Several treatment modalities for heavy menstrual bleeding are available. However, many women report being unsatisfied in their search for an appropriate and effective treatment. The aim of this study is to gain insights in the experienced impact of heavy menstrual bleeding and the motives and considerations of women during the decision-making process for treating heavy menstrual bleeding. METHODS: An interpretative qualitative study was performed, using in-depth interviews. In total, 14 semi-structured interviews were conducted with patients who consulted a physician for treatment of heavy menstrual bleeding. Participants were recruited via the Netherlands Patients Federation (N = 10) or via the outpatient clinic in the Máxima Medical Center (N = 4). The interviews were conducted by phone or online between February 2020 and March 2021. In the interviews three topics were addressed: (1) participant's experience with heavy menstrual bleeding, (2) experience with patient journey of treatment decision-making and (3) elaborating on alternative treatments for heavy menstrual bleeding. A thematic analysis was conducted. RESULTS: Fourteen participants aged between 30 and 59 years old were interviewed. Three main themes emerged; "Considerations in taking the (next) step to seek help", "Various sources of information can contribute, confuse or frighten decision-making process" and "A physician's understanding and a relationship of trust are needed to guide the decision-making process". CONCLUSION: Our results show that women's considerations and decision making strongly depend on the obtained information and experience, the relationship with the physician, the influence of the social environment, the pre-visit expectations/desires, the fear of treatment complications and uncertainty of the effect of the treatment. It is a physicians role to create a trusting and open atmosphere during consultation. Patient-centered communication is helpful to share knowledge, and gain insights into a patient's hopes, fears and worries.

Systematic review and meta-analysis of the etiology of heavy menstrual bleeding in 2,770 adolescent females.

BACKGROUND: Adolescent heavy menstrual bleeding(HMB), menorrhagia or abnormal uterine bleeding commonly occur in adolescent women. The differential diagnosis can be challenging. The pneumonic: PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified), is commonly used but it does not stratify as to the likelihood of a disorder. We have sought to develop a probability-based differential diagnosis for Adolescent HMB, menorrhagia or abnormal uterine bleeding. METHODS: A comprehensive literature search was conducted using PubMed, EMBASE, and SCOPUS databases. Case series describing adolescents from 10-19 years of age with HMB, menorrhagia or abnormal uterine bleeding was acceptable if: more than 10 patients were included; editorials, case reports, and secondary sources such as review articles, or book chapters were excluded. No language filter was used, but an English abstract was required. The etiology of HMB, menorrhagia or abnormal uterine bleeding, and the country of origin was extracted from articles that met inclusion criteria. Cumulative rate estimates were determined by Bayesian probability modeling. RESULTS: Seventeen full text articles were reviewed in detail; 2,770 patients were included. The most frequent causes of HMB were Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5%), Coagulation Disorders (19.4%; 95% CredI 17.8-21.1%), and Platelet Disorders (6.23%; 95% CredI 5.27-7.27%) with 45.9% (95% CredI 43.8-47.%9) of the cases of indeterminate origin. CONCLUSIONS: The leading causes of HMB in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of HMB. While PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of HMB in females, this systematic review assigns probabilities to the etiologies of HMB in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis.

Submucosal cystic adenomyosis: a report of five cases and review of the literature.

AIM: To investigate the clinical characteristics, diagnosis, and clinical treatment of submucosal cystic adenomyosis. METHODS: The clinical data of five cases of patients with submucosal cystic adenomyosis in our hospital from January 2020 to June 2023 were retrospectively analyzed. RESULTS: The average age of the patients was 37.8 ± 4.5 years old, three of them experienced prolonged menstruation and heavy menstrual bleeding. All patients had a history of abnormal uterine bleeding and mild to moderate dysmenorrhea, with a VAS score of 2.8 ± 1.6. The average Carbohydrate antigen 125 (CA125) value was 29.9 ± 23.6U/ml. Two out of the five patients (40%) had CA125 values above the upper limit of normal. The nodules had a diameter of 3.2 ± 1.3 cm and a cavity size of 1.3 ± 0.7 cm. Color ultrasound revealed hypo or iso or anechoic echoic cysts, and blood flow signals were detected. The magnetic resonance imaging (MRI) findings varied among each patient. All the patients underwent hysteroscopy and resection of uterine cavity-occupying lesions, and no recurrence was observed. CONCLUSIONS: The clinical features of submucosal cystic adenomyosis include abnormal uterine bleeding and menstrual changes, and the degree of dysmenorrhea is generally not severe. The diagnostic utility of CA125 in submucosal cystic adenomyosis may be limited. The three-dimensional ultrasound and MRI are valuable preoperative examination methods currently. Hysteroscopy can not only diagnose submucosal cystic adenomyosis, but also treat it, and preserve the fertility function of the patient.

The quality of life and work productivity are affected by the presence of nausea/vomiting in patients taking iron preparations for heavy menstrual bleeding or anemia: a population-based cross-sectional survey in Japan.

BACKGROUND: Patients with iron deficiency anemia are treated with iron preparations, but gastrointestinal symptoms such as nausea and vomiting occur frequently. These symptoms may negatively affect the quality of life and work productivity in patients with iron deficiency anemia. This study assessed the impact of nausea and vomiting on the quality of life and work productivity of patients taking iron preparations for heavy menstrual bleeding or anemia. METHODS: An online survey was conducted among patients taking iron preparations for heavy menstrual bleeding or anemia. Demographic data and information about medication use and the health condition were collected. The patients were asked to answer the 5-level EQ-5D version, and work productivity and activity impairment questionnaires. The outcomes were reported by patients in the presences of nausea, vomiting, and nausea or vomiting. The association with the 5-level EQ-5D version utility score for the severity and frequency of the symptoms were also assessed. RESULTS: A total of 385 patients were enrolled, and 96 were patients with nausea or vomiting, of which 94 were with nausea and 27 were with vomiting. The 5-level EQ-5D version utility scores for the patients with nausea, vomiting, and nausea or vomiting were significantly lower than those of the patients without these symptoms (p < 0.001 for each). The 5-level EQ-5D version utility score was correlated with the severity of nausea and the frequency of vomiting per day (p < 0.001 for each). As for the work productivity and activity impairment, the presenteeism, the overall work impairment, and the activity impairment of the patients with nausea, vomiting, and nausea or vomiting were significantly higher than those without these symptoms (p < 0.001 for each). The absenteeism was slightly higher trend was observed, but not significant. CONCLUSION: Patients taking iron preparations who have nausea or vomiting experience a significant burden in terms of poorer quality of life and higher work productivity impairment. TRIAL REGISTRATION: UMIN000045700 ( http://www.umin.ac.jp/ctr/ ). Registered on October 11, 2021.

Parity, mode of birth, and long-term gynecological health: A follow-up study of parous and nonparous women in the Australian Longitudinal Study on Women's Health cohort.

BACKGROUND: Although gynecological health issues are common and cause considerable distress, little is known about their causes. We examined how birth history is associated with urinary incontinence (UI), severe period pain, heavy periods, and endometriosis. METHODS: We studied 7700 women in the Australian Longitudinal Study on Women's Health with an average follow-up of 10.9 years after their last birth. Surveys every third year provided information about birth history and gynecological health. Logistic regression was used to estimate how parity, mode of birth, and vaginal tears were associated with gynecological health issues. Presented results are adjusted odds ratios (OR) with 95% confidence intervals. RESULTS: UI was reported by 16%, heavy periods by 31%, severe period pain by 28%, and endometriosis by 4%. Compared with women with two children, nonparous women had less UI (OR 0.35 [0.26-0.47]) but tended to have more endometriosis (OR 1.70 [0.97-2.96]). Also, women with only one child had less UI (OR 0.77 [0.61-0.98]), but more severe period pain (OR 1.24 [1.01-1.51]). Women with 4+ children had more heavy periods (OR 1.42 [1.07-1.88]). Compared with women with vaginal birth(s) only, women with only cesarean sections or vaginal birth after cesarean section had less UI (ORs 0.44 [0.34-0.58] and 0.55 [0.40-0.76]), but more endometriosis (ORs 1.91 [1.16-3.16] and 2.31 [1.25-4.28]) and heavy periods (ORs 1.21 [1.00-1.46] and 1.35 [1.06-1.72]). Vaginal tear(s) did not increase UI after accounting for parity and birth mode. CONCLUSION: While women with vaginal childbirth(s) reported more urinary incontinence, they had less menstrual complaints and endometriosis.