Menstrual Blood Loss Volume Research Articles

Limiting pre-menstrual endometrial Hypoxia Inducible Factor 2 Alpha may fine-tune endometrial function at menstruation.

Heavy menstrual bleeding (HMB) is common and debilitating, but the precise endometrial mechanisms causing increased menstrual blood loss (MBL) remain undefined. We have previously identified a role for hypoxia in endometrial repair following progesterone withdrawal. As hypoxia inducible factor 2 alpha (HIF2A) is known to alter vascular function in other tissues, we hypothesised that endometrial HIF2A is involved in pre-menstrual optimisation of endometrial function during the secretory phase to limit MBL. Women with objective HMB had higher endometrial HIF2A during the mid-secretory phase when compared to those with normal MBL (p=0.0269). In a mouse model of simulated menses, genetic or pharmacological manipulation of HIF2A did not significantly affect endometrial breakdown/repair, volume of MBL or endometrial hypoxia. However, 88% of Hif2a heterozygote mice reached early-full repair by 24h versus only 65% of wild-type mice. Mean MBL was 0.39 μl (±0.67) in Hif2a heterozygote mice versus 0.98 μl (±0.79) in wild-type mice. Conversely, when we increased HIF2A pre-menstrually, 11% reached early repair at by 8h versus 30% of vehicle-treated mice. Mean MBL was 2.61 μl (±1.10) in mice with HIF2A stabilisation and 2.24 μl (±1.14) in vehicle-treated mice. These non-significant but consistent trends indicate that increased endometrial HIF2A may contribute to delayed endometrial repair and HMB. Increased HIF2A in the secretory endometrium is unlikely to be sufficient to account for the phenotype of HMB, but limitation of HIF2 levels may optimise endometrial function at menstruation.

Treatment of uterine fibroid symptoms with relugolix combination therapy

Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormonereceptor 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.Result. 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.

Experience of using drospirenone/ethinyl estradiol combination in women of reproductive age

Introduction. A woman’s unwillingness to enter pregnancy due to social and somatic factors is associated with a high risk of its termination and concomitant complications. A personalized selection of a method of contraception is necessary, which best meets the needs of a woman, including in achieving non-contraceptive effects.Aim. To evaluate the effectiveness, safety and compliance indicators when using a combined drug (3 mg of drospirenone + 20 mcg of ethinyl estradiol) in women in the early and mature reproductive period.Materials and methods. A study involving 68 women (polycystic ovary syndrome (PCOS), n = 31, adenomyosis, n = 20, uterine fibroids, n = 7, a combination of 2 or more diagnoses) was conducted on the basis of the Scientific polyclinic Department of the V.I. Kulakov National Research Medical Center of the Ministry of Health of the Russian Federation) of reproductive age (18–34 years) who took a combined contraceptive drug for 6 months or more. The control of the results was carried out on the basis of monitoring in the form of a survey.Results. The average time of use of the drug was 9 (Q₁–Q₃: 8–11) months. After 3 and 6 months, 77.8% (21/27) and 100% of the observed patients, respectively, noted a decrease in the severity of PMS symptoms. 91.7% (n = 11/12) of patients noted a subjective decrease in the severity of acne and/or hirsutism after 6 months. 91.3% (n = 21/23) of women with copious painful menstruation noted normalization of the bleeding profile (volume of menstrual blood loss). 95.6% (65 patients out of 68) noted 100% compliance in the use of the drug.Conclusions. The drug Dimia has a favorable profile of clinical and pharmacological safety and efficacy, along with the complete reversibility of contraceptive action when actualizing the issue of the realization of reproductive function. The advantages of the drug are to achieve well-studied non-contraceptive effects, in which patients with PCOS, internal endometriosis and uterine fibroids are interested, in the form of relieving manifestations of PMS and reducing the severity of dysmenorrhea, as well as cosmetic skin imperfections (acne-type rashes, hirsutism). Thus, the drug can be recommended to women of reproductive age as a reliable contraceptive, as well as to achieve non-contraceptive effects.

Effect of topical application of a modified dosage form of granulocyte-colony stimulating factor in complex therapy of Ascherman syndrome

The effectiveness of the use of a modified intrauterine gel form of granulocyte colony stimulating factor in the complex treatment of Ascherman syndrome is evaluated. The study involved 31 patients with a history of Ascherman syndrome. For 6 months, the patients underwent weekly intrauterine administration of 1 ml of gel with a concentration of granulocyte colony stimulating factor of 9 million IU/ml using an intrauterine catheter. Monthly M-echo was evaluated on the 19th–22nd day of the menstrual cycle, as well as the volume of menstrual blood loss according to the Pictorial Blood Loss Assessment Chart. After the treatment was completed, a control hysteroscopy was performed. There is a statistically significant increase in M-echo from 2. 61 ± 1. 71 to 6. 52 ± 1. 23 mm (p 0. 001). At the same time, the proportion of patients with M-echo 6 and 7 mm increased from 6. 45 and 0% to 80. 65 and 51. 61, respectively, over the 6 months of the study. There is also a statistically significant increase in menstrual blood loss from 24. 9 ± 2. 6 to 53. 5 ± 3. 4 points on the Pictorial Blood Loss Assessment Chart (p 0. 001). A response to therapy was achieved in 17 patients, among them 12 patients were diagnosed with pregnancy that occurred spontaneously (17. 65%) or as a result of in vitro fertilization protocol (52. 9%). The data obtained indicate that intrauterine administration of a gel with granulocyte colony stimulating factor promotes endometrial regeneration in patients suffering from Ascherman syndrome, which is expressed in an increase in M-echo and the volume of menstrual blood loss. Thus, adjuvant use of a hydrogel with granulocyte colony stimulating factor and hyaluronic acid is an effective treatment option in restoring reproductive function and preventing recurrence of adhesiogenesis after surgical treatment of Ascherman syndrome. In general, the proposed gel form with granulocyte colony stimulating factor allows us to reduce the frequency of administration of the drug, which theoretically can increase both the compliance of patients primarily by reducing the number of invasive procedures, and reduce treatment costs.

Effects of antiplatelet therapy on menstrual blood loss in reproductive-aged women: a systematic review

BackgroundThe effects of antiplatelet therapy on menstrual bleeding have not been well characterized. ObjectivesTo systematically review the effects of antiplatelet therapy on menstrual bleeding. MethodsA literature search was performed for studies of reproductive-aged women who received antiplatelet therapy. Characteristics of menstrual bleeding both before and after initiation of antiplatelet therapy and from comparison groups were collected. Two reviewers independently assessed the risk of bias in individual studies. ResultsThirteen studies with a total of 611 women who received antiplatelet therapy were included. Types of antiplatelet drugs used were aspirin (n = 8), aspirin and/or clopidogrel (n = 2), prasugrel (n = 1), and not specified (n = 2). Risk of bias was assessed at moderate (n = 1), serious (n = 8), critical (n = 2), and no information (n = 2). Three studies reported changes in menstrual blood loss volume. One of these showed no increase during antiplatelet therapy; the other 2 studies suggested that aspirin may increase menstrual blood loss volume. In 3 studies that assessed the duration of menstrual bleeding, up to 13% of women reported an increased duration of menstruation. In 5 studies that reported the intensity of menstrual flow, 13% to 38% of women experienced an increase in the intensity of flow. Five studies reported the prevalence of heavy menstrual bleeding in women who received antiplatelet therapy, with estimates ranging from 7% to 38%. ConclusionThere is lack of high-quality data on the effects of antiplatelet therapy on menstrual bleeding. Aspirin may increase menstrual blood loss, at least in a minority of women, whereas the effects of P2Y12 inhibitors are unknown.

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

BackgroundIn the LIBERTY Long-Term Extension study, once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly improved uterine fibroid-associated heavy menstrual bleeding over the 52-week treatment period in the overall study population. Objectives(s)Black/African American women typically experience greater extent of disease and symptom burden of uterine fibroids versus 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/African American women with uterine fibroids in the LIBERTY Long-Term Extension study. Study designBlack/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 (NCT03049735) or LIBERTY 2 (NCT03103087) trials were eligible to enroll in the 28-week LIBERTY Long-Term Extension (NCT03412890), in which all women received once-daily, open-label relugolix combination therapy. The primary endpoint of this subanalysis was the proportion of Black/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 pivotal study baseline to the last 35 days of treatment by pivotal study randomized treatment group. Secondary outcomes included rates of amenorrhea, as well as changes in symptom burden and quality of life. ResultsIn total, 241/477 (50.5%) women enrolled into the LIBERTY Long-Term Extension study self-identified as Black or African American. In Black/African American women receiving continuous relugolix combination therapy for up to 52 weeks, 82.9% [n=58/70; 95% confidence interval: 72.0%, 90.8%] met treatment responder criteria for reduction in heavy menstrual bleeding (primary endpoint). A substantial reduction in menstrual blood loss volume from 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 due to uterine fibroid-associated symptoms was demonstrated, as well as improvements in health-related quality of life through 52 weeks. 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(s)Once-daily relugolix combination therapy improved uterine fibroid-associated heavy menstrual bleeding in the majority of Black/African American women who participated in the LIBERTY Long-Term Extension. The safety and efficacy profile of relugolix combination therapy in Black/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/African American women understand the efficacy and safety of relugolix combination therapy as a pharmacologic option for the management of uterine fibroid-associated symptoms.

Low-Dose Elagolix for the Treatment of Heavy Menstrual Bleeding in Patients With Uterine Leiomyomas: A Randomized Controlled Trial.

To evaluate the safety and efficacy of elagolix 150 mg once-daily monotherapy in patients with heavy menstrual bleeding associated with uterine leiomyomas. A phase 4, randomized, double-blind, placebo-controlled, 6-month treatment study was conducted in premenopausal patients aged 18-51 years with heavy menstrual bleeding (defined as menstrual blood loss greater than 80 mL during one menstrual cycle) associated with uterine leiomyomas. Patients were randomized 2:1 to receive elagolix 150 mg once daily or placebo. The primary endpoint was reduction in menstrual blood loss volume to less than 80 mL at the final month and at least a 50% reduction in menstrual blood loss volume from baseline to the final month. Of 82 randomized patients, 54 received elagolix 150 mg and 28 received placebo. With elagolix, 49.4% (95% CI 35.1-63.8%) of patients met the primary endpoint, compared with 23.3% (95% CI 7.2-39.5%) of patients who received placebo ( P =.035). Statistically significant differences between elagolix and placebo in mean reduction of menstrual blood loss from baseline were seen as early as month 1 ( P <.05 for months 1-3 and 5). Significantly more patients receiving elagolix experienced suppression of bleeding compared with placebo ( P =.036). Greater improvements were observed in the elagolix group (vs placebo) in the proportion of patients with amenorrhea, in hemoglobin concentrations, and in health-related quality of life. No serious or severe adverse events were reported for elagolix, compared with 7.1% of participants in the placebo group having serious adverse events (coronavirus disease 2019 [COVID-19] n=1, enlarged uvula n=1). Three patients (5.6%) discontinued elagolix due to adverse events. Elagolix 150 mg once-daily monotherapy significantly improved heavy menstrual bleeding associated with uterine leiomyomas compared with placebo in premenopausal patients. Treatment with elagolix 150 mg once daily was generally well-tolerated in this study, with no new safety signals. AbbVie Inc. ClinicalTrials.gov , NCT03886220.

Comparison of menstruation recovery after ultrasound-guided suction curettage in patients with cesarean scar pregnancy pretreated using high-intensity focused ultrasound and uterine artery embolization

Objectives To investigate the menstruation recovery after two therapeutic regimens, high-intensity focused ultrasound (HIFU) or uterine artery embolization (UAE) combined with ultrasound-guided suction curettage, for premenopausal women with cesarean scar pregnancy (CSP). Materials and methods Seventy patients with CSP treated with HIFU followed by ultrasound-guided suction curettage and 63 patients with CSP treated with UAE followed by ultrasound-guided suction curettage in our hospital were retrospectively reviewed. The treatment parameters and the menstrual blood loss (MBL) volume at 6 months after the two therapeutic regimens were compared between the two groups. Results There was no significant difference in treatment results between the two groups. With regard to postoperative MBL volume, 5 out of 70 patients in the HIFU group and 22 out of 63 patients in UAE group exhibited a reduction in MBL, respectively. Multivariate logistic regression revealed that hypomenorrhea was more likely to occur in the UAE group than in the HIFU group (UAE group vs. HIFU group; OR 11.328, 95% CI 3.158–55.871; p < 0.001). Conclusion Compared to UAE, HIFU has less influence on postoperative MBL volume, which may be a fertility-sparing option for patients with CSP.

LIBERTY randomized withdrawal study: relugolix combination therapy for heavy menstrual bleeding associated with uterine fibroids

In the pivotal LIBERTY 1 and 2 trials and long-term extension study, once-daily relugolix combination therapy (40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) reduced menstrual blood loss volume and pain among women with uterine fibroids. Relugolix combination therapy was well tolerated with preservation of bone mineral density through 52 weeks. This study aimed to report the 2-year relugolix combination therapy efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study. Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials, followed by the 28-week long-term extension study (up to 52 weeks total treatment), and who met the responder criteria (menstrual blood loss volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 [week 24 of long-term extension]) were randomized in a 1:1 ratio to either blinded treatment with relugolix combination therapy or placebo for 52 weeks (total treatment period, 104 weeks). For women who had a relapse of heavy menstrual bleeding during the study (menstrual blood loss volume ≥80 mL), open-label relugolix combination therapy was offered. The primary endpoint was the proportion of women who maintained menstrual blood loss volume <80 mL through week 76 (week 24 of randomized withdrawal study). Secondary endpoints included time to menstrual blood loss volume ≥80 mL, proportion of women who maintained a menstrual blood loss volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women who achieved or maintained amenorrhea at week 76 at the end of treatment, and the change in Uterine Fibroid Symptom-Quality of Life Bleeding and Pelvic Discomfort Scale and symptom severity scores. Analyses were performed for the modified intent-to-treat population, including all randomized women who received ≥1 dose of the study drug. Of the 229 randomized women (relugolix combination therapy, n=115; placebo, n=114), 228 received the study drug and 175 (76.7%) completed the randomized withdrawal study. Through week 76, 78.4% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 15.1% in the placebo group (difference, 63.4%; 95% confidence interval, 52.9%-73.9%; P<.0001). At week 104, 69.8% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 11.8% in the placebo group (difference, 58.0%; 95% confidence interval, 47.0%-69.1%; P<.0001). Through week 104, 88.3% of women on placebo relapsed with heavy menstrual bleeding (median time to relapse, 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix combination therapy with a menstrual blood loss volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference, 44.1%; 95% confidence interval, 33.10%-55.1%; P<.0001) and 58.3% vs 10.6% at week 104 (difference, 47.6%; 95% confidence interval, 37.0%-58.3%; nominal P<.0001) for relugolix combination therapy and the placebo group, respectively. Relugolix combination therapy was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density remained stable in women who received relugolix combination therapy from week 52 to week 104. In women continuously treated with relugolix combination therapy up to 2 years, bone mineral density was generally preserved. After 2 years of treatment with relugolix combination therapy, there was evidence of durability of the effect in maintaining low menstrual blood loss volume in women with symptomatic uterine fibroids. Most women had return of heavy menstrual bleeding and associated symptoms after treatment cessation, which improved upon retreatment with relugolix combination therapy. Relugolix combination therapy was well tolerated, the adverse event profile remained consistent, and the mean bone mineral density was generally preserved through 2 years of treatment.

Relugolix combination therapy in European women with symptomatic uterine fibroids: a subgroup analysis from the randomized phase 3 LIBERTY pivotal trials

Objective In the 24-week, phase 3 LIBERTY 1 (L1) and LIBERTY 2 (L2) trials, relugolix combination therapy (relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg)) reduced uterine fibroid (UF)-associated symptoms. This post hoc analysis assessed safety and efficacy of relugolix-CT in European women from L1/L2. Methods Premenopausal women (aged 18–50 years) with UF-associated heavy menstrual bleeding (HMB) were randomized 1:1:1 in L1 (N = 388) and L2 (N = 382) to relugolix-CT or placebo for 24 weeks, or delayed relugolix-CT (relugolix 40 mg then relugolix-CT; 12 weeks each). Primary endpoint: proportion of responders (menstrual blood loss (MBL) <80 mL and reduction of ≥50% from baseline MBL volume) over the last 35 days of treatment. Secondary endpoints: MBL volume, amenorrhea, UF-associated pain, symptom severity, distress related to bleeding and pelvic discomfort, health-related quality of life (HRQoL). Safety endpoints included adverse event (AE) reporting and bone mineral density (BMD) assessment. Results In European women from L1/L2 (N = 124, 16%), a significantly greater proportion of treatment responders was observed with relugolix-CT vs. placebo (85.4% vs. 19.1%, respectively; nominal p < .0001). There were statistically significant improvements with relugolix-CT vs. placebo for several secondary endpoints: reduction in MBL volume, amenorrhea rate, proportion achieving mild-to-no pain, reduction in symptom severity and distress from bleeding and pelvic discomfort, and improvement in HRQoL. Incidence of AEs and percentage changes in BMD from baseline to week 24 were similar for relugolix-CT and placebo. Conclusions In European women with UF and HMB, once-daily relugolix-CT vs. placebo improved UF-associated symptoms and preserved BMD.

Elagolix With Add-Back Therapy Improves Hemoglobin Concentration in Women With Fibroid-Associated Heavy Menstrual Bleeding Across Subgroups: Post Hoc Analysis of Elaris UF-1 and UF-2 [ID: 1368060

INTRODUCTION: Premenopausal patients with fibroid-associated heavy menstrual bleeding often experience anemia-related symptoms and reduced quality of life. Here, we report the effect of elagolix with estradiol/norethindrone acetate add-back therapy (ELA+AB) on hemoglobin (Hgb) concentration across subpopulations of patients at 6 months of treatment. METHODS: This post hoc analysis from duplicate, IRB-approved, randomized, double-blind, placebo-controlled, 6-month phase 3 Elaris UF-1/UF-2 studies (NCT02654054/NCT02691494) evaluated Hgb improvement from baseline to 6 months of therapy by change in Hgb concentration and proportion of patients who achieved greater than 1 and greater than 2 g/dL improvement by subgroups (race, age, primary International Federation of Gynecology and Obstetrics [FIGO] score, and baseline menstrual blood loss volume) in prespecified anemic subpopulations (baseline Hgb≤10.5 and 10.5 to ≤12 g/dL). RESULTS: Overall, baseline demographics and clinical characteristics were balanced between groups. Regardless of subgroup, patients with mean baseline Hgb less than 10.5 g/dL receiving ELA+AB experienced significant improvements in mean Hgb concentration at 6 months, compared with placebo (P&lt;.001; no adjustment for multiple comparisons were made). These patients had a mean Hgb concentration of 11.6 g/dL at 6 months, with a range of 11.3–12.3 g/dL depending on subgroup. At 6 months, 47% of these patients had an increase of greater than 2 g/dL with a range of 41–59% depending on subgroup. CONCLUSION: ELA+AB was effective in improving Hgb concentration across subgroups of premenopausal women with uterine fibroids and anemia (Hgb &lt;10.5 g/dL), regardless of baseline demographics or clinical characteristics, which may therefore alleviate symptoms and reduce complications of anemia.

Clinical assessment of the condition of women of reproductive age with adenomyosis after experiencing COVID-19

Annotation. The relevance of the gynecological disease adenomyosis (N80.0) is beyond doubt, as this pathology is a serious problem today both in medicine and in society. The aim is to study the clinical condition of women of reproductive age with adenomyosis after suffering COVID-19. 150 women of reproductive age were examined after suffering COVID-19 disease, 120 of them with adenomyosis. The results obtained were processed using the methods of mathematical statistics and using the MS Excel XP, Statistica 6.0 software package using Student's parametric test. At the same time, differences were considered statistically significant at p&lt;0.05. A clinical assessment of the condition of women of reproductive age with adenomyosis after suffering COVID-19 confirmed a significantly more severe course of adenomyosis in the early post-COVID period. After undergoing COVID-19, the frequency of complaints of general malaise, headaches, lethargy, pain in the joints, muscles, and pelvis in women aggravated by adenomyosis significantly increased. The more severe the degree of the disease (I-II, III-IV), the worse was the general condition of the examined patients. The frequency of complaints about general malaise, exacerbation of extragenital diseases (cardiovascular system, gastrointestinal tract, hepatobiliary system, anemia, etc.), gynecological pathology, including disorders of menstrual function, volume of menstrual blood loss, pelvic pain syndrome, presence of processes of inflammatory (infectious) etiology increased significantly. Determining the clinical assessment of the condition of women of reproductive age with adenomyosis after suffering COVID-19 is of fundamental practical importance for determining the tactics of managing this cohort of patients with the aim of timely qualified prevention of possible complications. Prospects for further research are aimed at developing and implementing an algorithm for managing women of reproductive age with adenomyosis after suffering COVID-19.

Аномальные маточные кровотечения и ожирение: современная парадигма

Abnormal uterine bleeding (AUB) remains one of the most common gynecological disorders that reduce the quality of life and reproductive potential in women. Obesity is recognized as an independent risk factor for the development of AUB associated with irregular endometrial proliferation (endometrial hyperplasia and endometrial cancer), ovulatory dysfunction and disease recurrence. The role of obesity in the pathogenesis of AUB due to endometrial dysfunction is an interesting and understudied aspect. Chronic adipose tissue inflammation is mechanistically linked to metabolic disease and organ tissue complications in overweight and obese women. Despite its minor nature, low-grade adipose tissue inflammation negatively impacts remote organ functions, thus being a cause of obesity complications. The results of recent studies suggest that obesity creates conditions for a proinflammatory environment in the endometrium during menstrual bleeding, which may inhibit endometrial regeneration and increase the volume of menstrual blood loss. Key words: abnormal uterine bleeding, obesity, chronic latent inflammation, endometrial dysfunction, endothelial dysfunction

Quality of life with relugolix combination therapy for uterine fibroids: LIBERTY randomized trials

Symptomatic uterine fibroids are burdensome to live with; they are associated with symptom-related distress, affect daily activities, and reduce health-related quality of life. The LIBERTY randomized clinical trials showed that oral relugolix combination therapy (40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate once daily) markedly improved fibroid-associated symptoms and conditions, including heavy menstrual bleeding, pain, and anemia, and was well-tolerated. This study aimed to evaluate the effect of relugolix combination therapy on the symptom burden and health-related quality of life among women with uterine fibroids. Two replicate, multinational, double-blind, 24-week, randomized, placebo-controlled, phase 3 studies, LIBERTY 1 and LIBERTY 2, were conducted in premenopausal women with uterine fibroid-associated heavy menstrual bleeding (≥80 mL per cycle for 2 cycles or ≥160 mL during 1 cycle). The symptom burden and health-related quality of life were secondary endpoints and were assessed using the validated Uterine Fibroid Symptom and Quality of Life questionnaire, which the participants completed at baseline and at week 12 and 24 of treatment. For this secondary analysis, the pooled LIBERTY 1 and LIBERTY 2 data set was used. The Uterine Fibroid Symptom and Quality of Life questionnaire is made up of a Symptom Severity scale and a Health-Related Quality of Life scale, the latter of which includes 6 subscales focusing on the following aspects of daily life: concern, activities, energy or mood, control, self-consciousness, and sexual function. The Revised Activities subscale of the Health-Related Quality of Life scale addresses the impact of uterine fibroids on physical and social activities. Symptom burden was also assessed via the Bleeding and Pelvic Discomfort subscale, a patient-reported outcome measure derived from the Uterine Fibroid Symptom Severity scale that focuses on distress from key uterine fibroid symptoms, which was a key secondary endpoint. Least squares mean changes from baseline to week 24 in the Symptom Severity scale, Bleeding and Pelvic Discomfort subscale, overall Health-Related Quality of Life scale, and the respective subscales were compared between the relugolix combination therapy and placebo groups. Responder analyses of the proportion of women who experienced a clinically meaningful change from baseline to week 24 were conducted for the Bleeding and Pelvic Discomfort and the activity subscales. A stratified Cochran-Mantel-Haenszel test, adjusted for stratification factors (region [North America vs rest of world] and baseline menstrual blood loss volume), was used for treatment comparisons. Across both trials, 509 women were randomized to the relugolix combination therapy or placebo groups (April 2017-December 2018). Participants on relugolix combination therapy showed a statistically significant reduction in symptom severity (-33.5 vs-12.1; nominal P<.0001) and the Bleeding and Pelvic Discomfort subscale from baseline to week 24 when compared with those on placebo treatment (-48.4 vs-17.4; nominal P<.0001). Overall, the total Health-Related Quality of Life scores improved significantly from baseline to week 24 in the relugolix combination therapy group when compared with the placebo (+37.6 vs+13.1; nominal P<.0001). Responder analyses demonstrated that more women treated with relugolix combination therapy reported a clinically meaningful reduction in the Bleeding and Pelvic Discomfort subscale and an improvement in physical and social activities when compared with those treated with the placebo (nominal P<.0001). After 24 weeks of treatment with relugolix combination therapy, women with symptomatic uterine fibroids experienced substantial improvements in health-related quality of life with all subscales showing improvement, including emotional well-being, physical and social activities, and sexual function. In addition, women reported substantial reductions in the overall symptom burden and distress caused by key fibroid-associated symptoms.

Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas.

In the LIBERTY 1 and LIBERTY 2 placebo-controlled trials, once-daily relugolix combination therapy reduced menstrual blood loss volume and pain in women with heavy menstrual bleeding associated with uterine leiomyomas and was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. Here we report the long-term efficacy and safety of relugolix combination therapy treatment for up to 52 weeks. Women with uterine leiomyoma-associated heavy menstrual bleeding who completed any treatment arm in either the LIBERTY 1 or LIBERTY 2 trial were eligible to enroll in a 28-week long-term extension study. All participants received once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) in the extension study. The primary efficacy endpoint was the proportion of women who achieved or maintained a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction in menstrual blood loss volume from LIBERTY study baseline to the last 35 days of treatment (defined as responders ). Analyses were conducted for all three randomized treatment groups from pivotal studies. Overall, 477 women enrolled, 476 were treated, and 363 (76.1%) completed 52 weeks. Among patients treated with relugolix combination therapy through 52 weeks (n=163), sustained improvement in heavy menstrual bleeding was observed in 87.7% (responders). The least squares mean menstrual blood loss volume reduction was 89.9%, with 70.6% of patients achieving amenorrhea. At week 52, 59.0% of patients with anemia at baseline had improvements in hemoglobin concentration of greater than 2 g/dL. Distress due to uterine leiomyoma-associated symptoms measured by the BPD (Bleeding and Pelvic Discomfort) scale score was reduced by 51.3 points. Sustained reductions in uterine and uterine leiomyoma volume were observed. Bone mineral density was preserved through week 52. Improvements in heavy menstrual bleeding and anemia and reduction of uterine leiomyoma-associated symptom burden were sustained through up to 52 weeks of treatment with relugolix combination therapy in women with uterine leiomyomas. No new safety concerns were identified, and BMD was maintained. ClinicalTrials.gov , NCT03049735; NCT03103087; NCT03412890. Myovant Sciences GmbH.

Relugolix Combination Therapy Improves Uterine Fibroid Symptoms Independent of Fibroid Location over 24 Weeks

<h3>Study Objective</h3> To evaluate the impact of fibroid location (submucosal, intramural, or subserosal) on treatment outcomes with relugolix combination therapy (Relugolix-CT) in women with uterine fibroid (UF)-associated heavy menstrual bleeding (HMB) in the LIBERTY 1 (L1) and LIBERTY 2 (L2) studies. <h3>Design</h3> L1 and L2 were replicate, Phase 3, double-blind, 24-week trials. <h3>Setting</h3> 80 (L1) and 99 (L2) research centers globally. <h3>Patients or Participants</h3> Premenopausal women (age 18–50 years) with diagnosed UF (confirmed on ultrasonography) and HMB (assessed by the alkaline hematin method). <h3>Interventions</h3> Participants were randomized to once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) or placebo for 24 weeks. <h3>Measurements and Main Results</h3> Fibroid location was investigator-defined using ultrasound; FIGO type 0/1 fibroids were excluded. Menstrual blood loss (MBL) volume was measured by alkaline hematin method (responders: MBL volume <80mL and ≥50% reduction from baseline over last 35 days of treatment). Pain and other UF-associated symptoms were evaluated using the Numerical Rating Scale and Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (Symptom Severity scale) in this <i>post-hoc</i> analysis<i>.</i> Pooled L1 and L2 data were used. In the Relugolix-CT (N=253) and placebo (N=256) groups, fibroid location was categorized as subserous (N=50 and N=58), intramural (N=115 and N=130), submucosal (N=46 and N=43) or "other/unknown" (N=119 and N=106). Overall, 136 women had >1 type of fibroid and were therefore included in >1 subgroup. Baseline characteristics, including MBL volume, pain and quality of life scores, were similar between subgroups. For each fibroid subgroup, respectively, women randomized to Relugolix-CT had comparable responder rates: 76.0%, 79.1%, 80.4%, and 65.6% at Week 24, which were higher than with placebo: 24.1%, 16.2%, 14.0%, and 16.0% (all nominal p<0.0001). Across all subgroups, Relugolix-CT resulted in significant reductions in MBL volume, UF-associated pain and Symptom Severity versus placebo. <h3>Conclusion</h3> Relugolix-CT improved HMB and other UF-associated symptoms through 24 weeks independent of fibroid location.

Interventions to prevent or treat heavy menstrual bleeding or pain associated with intrauterine-device use.

Interventions to prevent or treat heavy menstrual bleeding or pain associated with intrauterine-device use.

Relugolix Combination Therapy Improves Uterine Fibroid Symptoms Independent of Fibroid Location [A77

INTRODUCTION: In the Phase 3, replicate, institutional review board-approved LIBERTY 1 and 2 studies, relugolix combination therapy (Relugolix CT; once daily relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) improved uterine fibroid (UF)-associated heavy menstrual bleeding (HMB), pain, and quality of life (QoL). We report the impact of location (submucosal, intramural, or subserosal) of the largest fibroid on treatment outcomes through 24 weeks. METHODS: Premenopausal women were randomized to relugolix combination therapy or placebo for 24 weeks. Location of the largest fibroid was investigator-defined using ultrasound; FIGO type 0/1 fibroids were excluded. Menstrual blood loss (MBL) volume was measured by alkaline hematin method (responders: MBL volume &lt; 80mL and ≥50% reduction from baseline over last 35 days of treatment). Pain and other UF-associated symptoms were evaluated using the Numerical Rating Scale and UF-QoL Questionnaire (Symptom Severity) in this post-hoc analysis. RESULTS: In the relugolix combination therapy (N=253) and placebo (N=256) groups, the largest fibroid was categorized by location as subserous (N=50 and N=58), intramural (N=115 and N=130), submucosal (N=46 and N=43) or “other/unknown” (N=119 and N=106). Baseline characteristics, including MBL volume, pain and QoL scores, were similar between subgroups. In all fibroid subgroups, women randomized to relugolix combination therapy had comparable responder rates of 76.0%, 79.1%, 80.4%, and 65.6% at week 24 that were higher than with placebo: 24.1%, 16.2%, 14.0%, and 16.0% (all nominal P&lt;.0001). Across all subgroups, women randomized to relugolix combination therapy experienced significant reductions in MBL volume, UF-associated pain and symptom severity versus placebo. CONCLUSION: Relugolix combination therapy improves HMB and other UF-associated symptoms independent of the location of the largest fibroid.

Bleeding Patterns in Women With Uterine Fibroids Receiving Relugolix Combination Therapy Over 1 Year [A78

INTRODUCTION: In the institutional review board-approved LIBERTY 1 and 2 studies and long-term extension study, relugolix combination therapy (Relugolix-CT; once-daily relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) improved uterine fibroid (UF)-associated heavy menstrual bleeding (HMB). We analyzed bleeding patterns and bleeding intensity reported in a daily diary through 52 weeks/end of treatment. METHODS: Menstrual blood loss (MBL) volume was quantified by the alkaline hematin method. Amenorrhea was defined as lack of bleeding for two consecutive visits (approximately 56 days). Bleeding pattern was defined as cyclic (3–12 days of bleeding with ≤2 consecutive non-bleeding days within the menstruation duration) or irregular (did not meet the definition of amenorrhea or cyclic bleeding). Bleeding intensity was categorized as MBL volume of ≤80mL (including spotting, light and moderate bleeding) or &gt;80mL. RESULTS: In total, 163 women received relugolix combination therapy for up to 52 weeks. Of those, 70.6% reported amenorrhea. Smaller proportions of women reported cyclic or irregular patterns (9.2% and 20.2%, respectively). Of 15 patients with cyclic bleeding, nine experienced spotting or light/moderate bleeding (≤80mL) while five had &gt;80mL and one had no data. Similar intensity was observed among 33 women with irregular bleeding (≤80mL [15 women], &gt;80mL [10 women], and eight women had no data). CONCLUSION: The majority of women with UF-associated HMB who received relugolix combination therapy for up to 52 weeks achieved amenorrhea. Of the remaining women who had either cyclic or irregular bleeding, approximately half had spotting or light/moderate bleeding that was considered within the normal range for MBL (≤80mL).

Эффективность и безопасность комбинированного контрацептива с хлормадинона ацетатом при обильных менструальных кровотечениях и дисменорее в реальной клинической практике

This article presents the results of the prospective study involving 70 patients of reproductive age with heavy menstrual bleeding (HMB) and dysmenorrhea, interested in reliable contraception. Objective. To study the safety and efficacy of the low-dose combined oral contraceptive (COC) containing chlormadinone acetate (CMA) for the treatment of dysmenorrhea and HMB in real clinical practice. Patients and methods. Among 90 women who sought a method of contraception, we identified a group of 70 patients aged 18–45 years (mean age = 31.0 ± 7.7 [95% CI 29.2–32.9]) with complaints for HMB (n = 23) and/or dysmenorrhea (n = 65): primary (n = 37) and secondary (n = 28). For contraception, COC containing 0.03 mg ethinyl estradiol and 2 mg CMA was recommended. After 3 months, the dynamics of the volume of menstrual blood loss, pain severity (according to the Numeric Rating Scale (NRS)), as well as the frequency of side effects were assessed. Results. Among 90 women of reproductive age, 70 (78%) had HMB and/or dysmenorrhea of varying severity. After 3 months of using a low-dose CMA-containing COC, 87% of patients with HMB showed a statistically significant decrease in menstrual blood loss (p &lt; 0.001); in 72% of patients, a significant decrease in pain severity was observed: mean NRS value before taking COC was 6.2 ± 2.1 [95% CI 5.7–6.7]), it decreased to 3.5 ± 1.8 [95% CI 3.0-3.9]) (p &lt; 0.001) after 3 months. There were no significant differences in efficacy between the groups with primary and secondary dysmenorrhea. Conclusion. The prevalence of HMB and dysmenorrhea in a random sample of women of reproductive age is consistent with the data of systematic reviews (26% and 72%, respectively). The results obtained in real clinical practice confirm the additional therapeutic efficacy of the low-dose CMA-containing COC in HMB and dysmenorrhea. The frequency and severity of side effects during the COC use do not depend on the initial body mass index, but with an increase in the waist-to-hip ratio, there is a tendency to reduce the chance of developing side effects of using COC, which corresponds to the data on the metabolic neutrality of chlormadinone. Key words: chlormadinone, heavy menstrual bleeding, dysmenorrhea