Stewart, Elizabeth A.

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.

Abstract Study question What does the collaborative document on adenomyosis terminology, classification, and diagnosis by ESGE, ESHRE, and WES provides? Summary answer This good practice recommendations paper offers guidance on the technical aspects, terminology, classification, and diagnosis of adenomyosis in women of reproductive age. What is known already The existing literature on adenomyosis terminology is heterogeneous and confusing. Various classification systems based on ultrasound and MRI have been proposed, yet none have gained international acceptance or clinical validation. The contradictory data on the diagnostic accuracy of these modalities further complicate adenomyosis diagnosis in reproductive-age women. Study design, size, duration A working group from ESGE, ESHRE, and WES has collaborated to write recommendations concerning the terminology, classification, and diagnosis of adenomyosis. Participants/materials, setting, methods Focusing on terminology, classification, and diagnosis, this good practice paper paves the way for further recommendations on the management and surgical treatment of adenomyosis in reproductive-age women. Main results and the role of chance The document overviews adenomyosis terminology and reviews proposed classification systems based on histology, ultrasound, and MRI, concluding with diagnostic recommendations. Limitations, reason for caution Owing the scarcity of evidence, these recommendations predominantly rely on clinical expertise. Wider implications of the findings The recommendations aim to enhance existing adenomyosis guidelines. Study funding/Competing interests All costs were covered by ESHRE funds, with no external funding for the development process or manuscript production.

What is this summary about? This is a summary of findings from two research studies (known as clinical trials). The studies looked at how well a medicine called relugolix combination therapy worked in women with heavy menstrual bleeding (heavy bleeding during a period) with uterine fibroids (noncancerous or benign growths in the uterus). In this analysis of the studies, researchers looked at how patients self-reported their uterine fibroid symptoms before and after taking relugolix combination therapy. Researchers also looked at how patients self-reported the impact of uterine fibroids on their health-related quality of life before and after taking relugolix combination therapy. What were the results? Women took either relugolix combination therapy or placebo (a pill that contains no medicine) by mouth once daily for 24 weeks. Women completed the Uterine Fibroid Symptom and Quality of Life questionnaire (where “quality of life” refers to the women's health-related quality of life related to uterine fibroids) before, during, and after treatment. The questionnaire let researchers see if the women felt that relugolix combination therapy decreased the burden of uterine fibroid symptoms and improved the women's health-related quality of life related to uterine fibroids. More women said that they felt less distress due to their uterine fibroid symptoms and that their health-related quality of life related to uterine fibroids was better after taking relugolix combination therapy compared with women who took placebo. What do the results mean? Relugolix combination therapy may lessen distress associated with uterine fibroid symptoms and improve health-related quality of life related to uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80 ml) per cycle for two cycles or about two-thirds of a cup of blood (160 ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1 year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52 weeks 149 women took relugolix alone for 12 weeks followed by relugolix combination therapy for 40 weeks 164 women took placebo for 24 weeks followed by relugolix combination therapy for 28 weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1 year of treatment. Clinical Trial Registration: NCT03049735 ( ClinicalTrials.gov ) (LIBERTY 1) Clinical Trial Registration: NCT03103087 ( ClinicalTrials.gov ) (LIBERTY 2) Clinical Trial Registration: NCT03412890 ( ClinicalTrials.gov ) (LIBERTY extension study)

Background: Females with uterine fibroids (UF), benign tumors of the myometrium, have a higher risk of hypertension than females without UF. The relationship between UF and hypertension is not fully understood. Case studies have reported hypertension in patients with large UF that compress the ureters, resulting in hydronephrosis. However, this pathophysiology is not present in all females with UF and hypertension. It is unknown if UF volume is correlated with blood pressure in the absence of renal compromise. Therefore, the goal of this study was to determine the potential associations between blood pressure and 1) volume of the largest UF and 2) volume of the uterus (a surrogate for total UF volume) in females with UF. Methods: We utilized the Mayo Clinic Data Explorer to identify patients, who had pelvic ultrasound or magnetic resonance imaging (MRI) studies performed at Mayo Clinic-Rochester in 2021 that reported the presence of UF, and who were ages 18-65 years old. From this system, we collected brachial blood pressure data (systolic, diastolic, and mean), assessed in the outpatient setting within 14 days of imaging. For each patient, dimensions of the largest UF and the uterus were abstracted from radiology reports. The largest UF was assessed, as it reliably had all three dimensions reported. Volume of the uterus was used as a surrogate for total UF volume to consider the possibility of multiple UF that were not detailed in the radiology report. Volumes of the largest UF and uterus were each calculated as for ellipsoid structures, (length✕depth✕width)✕0.523 in cm3. The Pearson correlation coefficient (r) was calculated to assess the linear relationship between blood pressure and largest UF volume, and blood pressure and uterine volume. A p-value <0.05 denoted statistical significance. Results: One hundred thirteen females (48±9 years old) were included in the analysis, 88 with ultrasound and 25 with MRI reports. Average blood pressures were as follows, systolic: 121±16 mmHg (range: 92-185 mmHg), diastolic: 76±9 mmHg (52-101 mmHg), and mean: 91±11 mmHg (67-129 mmHg). Twenty-nine females (25.7%) had a diagnosis of hypertension. Hydronephrosis was not reported in any of the imaging reports. A mean of 2±2 UF were present per uterus (range: 1-15). Average volume of the largest UF was 75.0±115.9 cm3. Largest UF volume was not associated with systolic (r=0.023, p=0.812), diastolic (r=-0.040, p=0.677), or mean (r=-0.014, p=0.881) blood pressures. Average volume of the uterus was 219.6±215.6 cm3. Volume of the uterus was not associated with systolic (r=0.040, p=0.688), diastolic (r=0.102, p=0.305), or mean (r=0.071, p=0.475) blood pressures. Conclusion: In females with UF, blood pressure is not associated with the largest UF or uterine volumes. These data suggest that in the absence of hydronephrosis, the association between UF and blood pressure is not related to UF size. It is unknown if these findings differ based on factors, such as race. AHA 898649, NIH K01 HL1148144 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Hysterectomy, oophorectomy, and tubal ligation are common surgical procedures. The literature regarding cardiovascular disease (CVD) risk after these surgeries has focused on oophorectomy with limited research on hysterectomy or tubal ligation. Materials and Methods: Participants in the Nurses' Health Study II ( n = 116,429) were followed from 1989 to 2017. Self-reported gynecologic surgery was categorized as follows: no surgery, hysterectomy alone, hysterectomy with unilateral oophorectomy, and hysterectomy with bilateral oophorectomy. We separately investigated tubal ligation alone. The primary outcome was CVD based on medical-record confirmed fatal and nonfatal myocardial infarction, fatal coronary heart disease, or fatal and nonfatal stroke. Our secondary outcome expanded CVD to include coronary revascularization (coronary artery bypass graft surgery, angioplasty, stent placement). Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) and were adjusted a priori for confounding factors. We investigated differences by age at surgery (≤50, >50) and menopausal hormone therapy usage. Results: At baseline, participants were on average, 34 years old. During 2,899,787 person-years, we observed 1,864 cases of CVD. Hysterectomy in combination with any oophorectomy was associated with a greater risk of CVD in multivariable-adjusted models (HR hysterectomy with unilateral oophorectomy:1.40 [95% CI: 1.08–1.82]; HR hysterectomy with bilateral oophorectomy:1.27 [1.07–1.51]). Hysterectomy alone, hysterectomy with oophorectomy, and tubal ligation were also associated with an increased risk of combined CVD and coronary revascularization (HR hysterectomy alone: 1.19 [95% CI: 1.02–1.39]; HR hysterectomy with unilateral oophorectomy: 1.29 [1.01–1.64]; HR hysterectomy with bilateral oophorectomy: 1.22 [1.04–1.43]; HR tubal ligation: 1.16 [1.06–1.28]). The association between hysterectomy/oophorectomy and CVD and coronary revascularization risk varied by age at gynecologic surgery, with the strongest association among women who had surgery before age 50 years. Conclusion: Our findings suggest that hysterectomy, alone or in combination with oophorectomy, as well as tubal ligation, may be associated with an increased risk of CVD and coronary revascularization. These findings extend previous research finding that oophorectomy is associated with CVD.

Purpose of review Uterine fibroids is a common problem in reproductive-age individuals, frequently causing abnormal uterine bleeding, bulk symptoms, and adverse reproductive outcomes. Traditionally, almost half of the women with symptomatic fibroids received surgery for definitive treatment. There are a growing number of nonsurgical options for treatment that have become available for patients who desire conservative treatment or those with contraindications to surgery. Recent findings The introduction of oral gonadotropin-releasing hormone antagonists in combination with low-dose physiologic hormonal therapy demonstrated improvement in heavy menstrual bleeding, pain, and quality of life with preservation of bone density and a modest reduction in uterine volume with few hypogonadal side effects. Magnetic resonance-guided focused ultrasound surgery and uterine artery embolization continue to be minimally invasive procedural alternatives to hysterectomy that are safe and effective. Summary As more options for conservative management of uterine fibroids became available, it is important to counsel patients on possible options based on the size, location, and number of the fibroids as well as severity of the symptoms, plans for pregnancy, how close they are to menopause and their treatment goals.