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.

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.

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.

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.

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.

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.

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.

Analysis of related factors influencing postoperative recurrence of adenomyosis treated with HIFU.

OBJECTIVE: To analyze the efficacy of high-intensity focused ultrasound (HIFU) for adenomyosis and postoperative recurrence and its influencing factors. METHODS: Clinical and follow-up data of 308 patients with adenomyosis who were treated with HIFU in Haifu Center, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine from September 2017 to January 2022 were retrospectively analyzed. The recurrence of adenomyosis and the efficacy of HIFU at 6 months after surgery were followed up. To explore factors influencing postoperative prognosis and recurrence, the following variables were analyzed: patients' age, course of disease, gravidity and parity, size of the uterus, duration of HIFU, duration of irradiation, treatment intensity, dysmenorrhea score, time of follow-up, combined treatment of traditional Chinese medicine (TCM), western medicine adjuvant treatment, lesion location and type, and menorrhagia. RESULTS: Among the 308 patients, 238 (77%) were followed up from 6 to 36 months, with an average follow-up time of 15.24 ± 9.97 months. The other 70 (23%) were lost to follow-up. At 6-month after surgery, efficacy rates of dysmenorrhea and menorrhagia management were 86.7% and 89.3%, respectively. Postoperative recurrence rates were 4.8% (1-12 months), 9.0% (12-24 months), and 17.0% (24-36 months) for dysmenorrhea; and 6.3% (1-12 months), 2.4% (12-24 months), and 12.2% (24-36 months) for menorrhagia. Multivariate logistic regression analyses showed that parity (P = 0.043, OR = 1.773, 95% CI 1.018-3.087), uterine size (P = 0.019, OR = 1.004, 95% CI 1.001-1.007), combined treatment of TCM (P = 0.047, OR = 1.846, 95% CI 1.008-3.381), diffuse lesion type (P = 0.013, OR = 0.464, 95% CI 0.254-0.848) and ablation rate (P = 0.015, OR = 0.481, 95%CI 0.267-0.868) were prognostic factors (P < 0.05). Age, course of disease, gravidity, duration of HIFU, duration of irradiation, treatment intensity, preoperative dysmenorrhea score, time of follow-up, western medicine adjuvant therapy, lesion location, and preoperative menstrual volume had no effect on prognosis (P > 0.05). CONCLUSION: HIFU can effectively relieve dysmenorrhea and reduce menstrual volume in patients with adenomyosis. Parity, uterine size, lesion type (diffuse), and ablation rate are risk factors for symptom recurrence after HIFU, while the combination of TCM therapy is a protective factor for relapse. We, therefore, recommend TCM in the adjuvant setting after HIFU according to patient condition.

Increasing utilization of intrauterine device insertion at hysteroscopic endometrial evaluation for patients with endometrial hyperplasia.

PURPOSE: To examine the utilization and characteristics related to the use of hysteroscopy at the time of endometrial evaluation for endometrial hyperplasia in the outpatient surgery setting. METHODS: This cross-sectional study queried the Healthcare Cost and Utilization Project's Nationwide Ambulatory Surgery Sample. The study population was 3218 patients with endometrial hyperplasia who underwent endometrial evaluation from January 2016 to December 2019. Performance and clinical characteristics of hysteroscopic endometrial evaluation were assessed with multivariable binary logistic regression models. RESULTS: A total of 2654 (82.5%) patients had hysteroscopic endometrial tissue evaluation. Patients with postmenopausal bleeding, heavy menstrual bleeding, and polycystic ovary syndrome were more likely to undergo hysteroscopic endometrial evaluation in multivariable analysis (all, adjusted-P < 0.001). Uterine injury occurred in 4.9 per 1000 hysteroscopic endometrial evaluations; none had uterine injury in the non-hysteroscopy cohort. Among the 2654 patients who had hysteroscopic endometrial evaluation, 106 (4.0%) patients had intrauterine device insertion at surgery, and the utilization increased from 2.9 to 5.8% during the study period (P-trend < 0.001). Younger age, more recent year surgery, and obesity were independently associated with increased utilization of intrauterine device insertion at hysteroscopic endometrial evaluation (all, adjusted-P < 0.05). Among 2023 reproductive-age patients with endometrial hyperplasia, 1666 (82.4%) patients underwent hysteroscopic endometrial evaluation. On multivariable analysis, patients with heavy menstrual bleeding were more likely to have hysteroscopic endometrial evaluation (adjusted-P < 0.05). Intrauterine device insertion increased from 3.7% in 2016 to 8.0% in 2019 (P-trend = 0.007). CONCLUSION: This nationwide analysis suggests that the insertion of intrauterine devices at the time of hysteroscopic endometrial tissue evaluation for endometrial hyperplasia is increasing among reproductive-age population.

Hysteroscopic diode laser myolysis: from a case series to literature review of incisionless myolysis techniques for managing heavy menstrual bleeding in premenopausal women.

PURPOSE: This case series examined the safety and effectiveness of hysteroscopic myolysis using laser-induced interstitial thermo-therapy (LITT) for treating heavy menstrual bleeding (HMB) in premenopausal women with FIGO type 1 or 2 uterine fibroids, not planning for future fertility. Additionally, a comprehensive review of innovative, minimally invasive, incisionless myolysis techniques was conducted. METHODS: Women with HMB, sonographically diagnosed with a single FIGO type 1 or 2 fibroid, underwent hysteroscopic myolysis using the Leonardo® diode laser. Effectiveness was assessed via transvaginal ultrasound measurement of myoma size, volume and vascularization pre and post-procedure. Moreover, we also evaluated any improvements in symptoms using the Pictorial Blood Loss Assessment Chart (PBAC score) scores. RESULTS: The procedure resulted in significant HMB reductions and noticeable fibroid size, volume, and vascularization decrease in all three patients, with no reported complications. The literature review revealed both advantages and limitations of the minimally invasive, incisionless myolysis techniques. CONCLUSIONS: Hysteroscopic laser myolysis is a safe and effective therapeutic intervention for patients experiencing HMB, diagnosed with FIGO type 1 or 2 fibroids, and not planning for future fertility. The procedure resulted in significant reductions in menstrual blood loss and fibroid size. Despite the promising results, it is essential to note the limitations of this report, including its case series design, a small number of patients, and a short follow-up period. Further research is necessary to confirm these results.

Menstrual Changes Following COVID-19 Vaccination: A Cross-Sectional Study.

Background and Objectives: Menstrual changes, including altered cycle length and bleeding patterns, have been reported following COVID-19 vaccination. This study aimed to determine the prevalence and types of menstrual changes occurring after COVID-19 vaccination among female students and staff at a university in Saudi Arabia. Materials and Methods: A cross-sectional study was conducted among women aged 18-39 years who received at least one dose of a COVID-19 vaccine. Eligible participants, including university students and staff, were recruited between May 2022 and November 2022. Participants completed a questionnaire detailing their sociodemographic characteristics, general medical and reproductive history, and menstrual characteristics before and after vaccination. The prevalence of various menstrual changes (cycle length, bleeding days, flow, and mid-cycle spotting) was calculated. The demographic factors associated with menstrual changes were analyzed using chi-squared tests. Results: The 472 included participants had a mean age of 20.9 years, and 95.3% were unmarried. Changes in menstrual cycle characteristics after COVID-19 vaccination were reported by 54.7% of respondents overall. The most common change was in cycle length, followed by the number of menstruation days and bleeding flow. Menstrual changes were not associated with age, BMI, occupation, marital status, or medical history. Changes in intermenstrual bleeding were more frequently reported after the third dose of the Pfizer vaccine compared to the Moderna vaccine (p = 0.014). Conclusions: More than half of the recruited female students and staff reported menstrual changes following COVID-19 vaccination, with altered cycle length being the most common. The potential underlying mechanisms and implications of these menstrual alterations require further investigation. These findings provide evidence of the menstrual side effects of COVID-19 vaccines among women in Saudi Arabia.

Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. METHODS: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. FINDINGS: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups). INTERPRETATION: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. FUNDING: ObsEva.

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).