Impact of demographic and clinical factors on elagolix plus add-back therapy effects on patient-reported nonbleeding symptoms in women with heavy menstrual bleeding and uterine fibroids: a post hoc analysis of data from two clinical trials.

Objective: To investigate the efficacy of elagolix plus add-back therapy (estradiol [1 mg] and norethindrone acetate [0.5 mg] once daily) on patient-reported nonbleeding symptoms and menstrual bleeding associated with uterine fibroids (UFs) across different subpopulations. Design: Post hoc analysis of two phase 3 clinical trials-Elaris UF-1 and UF-2. Setting: A total of 76 (UF-1) and 77 (UF-2) US clinical sites. Patients: Women (N = 591) with UFs and heavy menstrual bleeding. Interventions: Elagolix (300 mg) twice daily with add-back therapy (the indicated dose for UF-associated heavy menstrual bleeding) vs. placebo for 6 months. Main Outcome Measures: "Very much improved" or "much improved" change in nonbleeding symptoms (abdominal/pelvic pain, abdominal/pelvic pressure/cramping, back pain, and abdominal bloating) and menstrual bleeding measured using a Patient Global Impression of Change scale. Improvements were assessed in subpopulations stratified using baseline characteristics (age, race [self-reported], body mass index, and International Federation of Gynecology and Obstetrics fibroid classification). Results: Across subpopulations, differences favored elagolix plus add-back therapy (vs. placebo) for most symptoms at month 1 and all symptoms at months 3 as well as 6. In patients with characteristics commonly associated with high disease burden (age >40 years, Black/African American), those treated with elagolix plus add-back therapy reported significantly greater improvements vs. placebo at months 1-6 (P<.05) for all nonbleeding and bleeding symptoms (P≤.05). Conclusions: Premenopausal women with heavy menstrual bleeding and UFs receiving elagolix plus add-back therapy experienced significant improvements in nonbleeding as well as bleeding symptoms from months 1-6, regardless of baseline characteristics. Clinical Trial Registration Number: NCT02654054 and NCT02691494.

Risks of Long-Term Psychiatric Disease in Women with a History of Primary Infertility: A Historical Cohort Study.

To examine the risks of long-term de novo psychiatric disease in women with primary infertiltiy compared to age-matched referrent women. Retrospective, population-based cohort of 1,001 women with primary infertility and 1,001 age-matched (± 1 year) referent women aged 18-50. The "index date" was date of first clinical note for infertility and included visits fromJanuary 1, 1980 to December 31, 1999. Baseline characteristics were collected by chart review. Outcome data was evaluated through December 31, 2020. Primary outcomes were baseline prevalence and de novo rates of subsequent psychiatric disorders including depression, anxiety, bipolar disorder, substance abuse, suicidality, and somatization evaluated by Cox proportional hazards modeling. Among women with primary infertility and referent women, the median duration of follow-up was 23.7 years. The risk of de novo psychiatric disorders was not significantly different between groups. Additionally, the risk of de novo psychiatric disorders did not significantly differ between those with isolated male factor versus isolated female factor infertility. Among women with primary infertility, the cumulative incidence of de novo depression and anxiety was significantly higher among women diagnosed with primary infertility in the 1990s compared to the 1980s. Women with primary infertility, in a historical population-based cohort, do not have a significantly different long-term risk of de novo psychiatric diagnoses compared to age-matched referent women. Our findings support the notion that infertility diagnosis and treatment present an acute period of stress and for some psychologic distress, neither of which persist or increase the risk for development of future psychiatric disease.

A plain language summary describing changes in pain associated with uterine fibroids among women receiving relugolix combination therapy.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. These studies compared how well a medicine called relugolix combination therapy and placebo worked in reducing heavy menstrual bleeding (periods) in women with uterine fibroids (published in a separate article referenced in the section: Where can readers find more information on these studies?). Researchers also looked at whether women with moderate to severe pain from uterine fibroids saw improvement in their worst pain symptoms after 24 weeks of treatment (results described in the present summary). WHAT ARE THE KEY TAKEAWAYS?: Women with moderate to severe pain from uterine fibroids (menstrual or nonmenstrual pain) took either relugolix combination therapy or placebo (once daily by mouth) for 24 weeks. During the last 5 weeks of treatment, 65% of women taking relugolix combination therapy and 19% of women taking placebo reported having minimal or no menstrual pain. Similarly, 45% of women taking relugolix combination therapy and 22% of women taking placebo reported having minimal or no non-menstrual pain. During the same time period, 71% of the women taking relugolix combination therapy and 40% of women taking placebo reported their worst pain was reduced by about one third compared with the start of the study. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Women with moderate to severe pain from uterine fibroids taking relugolix combination therapy were more likely to have minimal or no pain from uterine fibroids after treatment compared with women taking placebo.Clinical Trial Registration: NCT03049735 (LIBERTY 1), NCT03103087 (LIBERTY 2) (ClinicalTrials.gov).

ACR Appropriateness Criteria® Management of Uterine Fibroids: 2023 Update.

Uterine fibroids are the most common benign tumor in women of reproductive age and can present with symptoms including bleeding, bulk related symptoms, and infertility. Several treatment options are available for the management of uterine fibroids, including medical management, minimally invasive therapies such as uterine artery embolization and MR-guided focused ultrasound ablation, and surgical interventions ranging from laparoscopic myomectomy to open hysterectomy. Given this wide range of therapeutic interventions, it is important to understand the data supporting these interventions and to be able to apply it in different clinical settings. This document provides a summary of recent trials supporting various therapies for uterine fibroids, including recent evidence for MR-guided focused ultrasound ablation and a detailed discussion of fertility outcomes in myomectomy and uterine fibroid embolization. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Changes in symptom burden and quality of life among women with uterine fibroids receiving relugolix combination therapy: a plain language summary.

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.

"In our community, we normalize pain": discussions around menstruation and uterine fibroids with Black women and Latinas.

BACKGROUND: Uterine fibroids are non-cancerous neoplasms that arise from the uterus affecting over 75% of women. However, there is a disparity with Black women having an increased prevalence of nearly 80%. Black women also experience increased symptom burden, including younger age at the time of diagnosis and increased number and volume of fibroids. Less is known about other ethnoracially diverse women such as Latinas and the potential cultural impacts on fibroid burden and treatment. METHODS: Community engagement studios were conducted to facilitate discussions with stakeholders on their uterine fibroid and menstruation experience. We recruited Black women (n = 6) diagnosed with uterine fibroids and Latinas (n = 7) without uterine fibroids. We held two virtual community engagement studios split by uterine fibroid diagnosis. The studios were not audio recorded and notes were taken by four notetakers. The notes were thematically analyzed in Atlas.ti using content analysis. RESULTS: Participants felt there was a lack of discussion around menstruation overall, whether in the home or school settings. This lack of menstruation education was pronounced when participants had their first menstruation experience, with many unaware of what to expect. This silence around menstruation led to a normalization of painful menstruation symptoms. When it came to different treatment options for uterine fibroids, some women wanted to explore alternative treatments but were dismissed by their healthcare providers. Many participants advocated for having discussions with their healthcare provider about life goals to discuss different treatment options for their uterine fibroids. CONCLUSION: Despite uterine fibroid diagnosis, there is silence around menstruation. Menstruation is a normal biological occurrence and needs to be discussed to help prevent delayed diagnosis of uterine fibroids and possibly other gynecological disorders. Along with increased discussions around menstruation, further discussion is needed between healthcare providers and uterine fibroid patients to explore appropriate treatment options.

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

Prevalence and impact of fertility concerns in young women with breast cancer.

Survey data from the Mayo Clinic Breast Disease Registry were used to assess fertility counseling and fertility preservation strategies in a modern cohort of young women with breast cancer. One hundred respondents were identified who were under age 50 at the time of breast cancer diagnosis and who expressed interest in future childbearing near the time of diagnosis and/or 1 year later. Ninety-three percent of the 81 respondents to the year one survey recalled fertility counseling prior to cancer treatment. Most who reported a high level of fertility concern declared that this concern had impacted their treatment decisions, often shortening their planned duration of endocrine therapy. Approximately half had taken steps to preserve future fertility, and a third had used a gonadotropin-releasing hormone agonist either alone or combined with another method (e.g., embryo or oocyte cryopreservation).

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 plain language summary of the long-term relugolix combination therapy study for 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).

Cost-effectiveness of Myomectomy versus Hysterectomy in Women with Uterine Fibroids.

STUDY OBJECTIVE: Increasing evidence suggests that hysterectomy to treat uterine fibroids (UFs), even with ovarian conservation (OC), is associated with a 33% increased risk of coronary artery disease (CAD). We sought to compare the cost-effectiveness of various treatment approaches for UFs to understand the trade-offs among development of CAD vs new fibroids. DESIGN: We developed a Markov model to include women with UFs who no longer desired pregnancy. The outcomes of interest were quality-adjusted life-years (QALYs) and total treatment costs. We conducted sensitivity analyses to test the effect of uncertain model inputs. SETTING: Health system perspective. PATIENTS: A hypothetical cohort of 10 000 40-year-old women. INTERVENTIONS: Myomectomy, hysterectomy with OC, and hysterectomy without OC. MEASUREMENTS AND MAIN RESULTS: Myomectomy was the best-value strategy, costing US$528 217 and providing 19.38 QALYs. Neither hysterectomy with OC nor hysterectomy without OC was found to be cost-effective, assuming a willingness-to-pay threshold of $100 000 per QALY gain as hysterectomy with OC provided more benefit than myomectomy at an average cost of $613 144 to gain one additional QALY. The sensitivity analyses showed that if the risk of new symptomatic UFs that required treatment after myomectomy was more than 13%, annually (base case, 3.6%), or the quality of life after myomectomy was less than 0.815 (base case, 0.834), then myomectomy would no longer be cost-effective, under a willingness-to-pay amount of US$100 000. CONCLUSION: Myomectomy is an optimal treatment of UFs compared with hysterectomy among women aged 40 years. The increased risk of CAD after hysterectomy and its associated costs and the effects on morbidity and quality of life made hysterectomy a costlier and less effective long-term strategy.

A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

Long-term health-related quality of life and symptom severity following hysterectomy, myomectomy, or uterine artery embolization for the treatment of symptomatic uterine fibroids.

BACKGROUND: Few studies have directly compared different surgical procedures for uterine fibroids with respect to long-term health-related quality of life outcomes and symptom improvement. OBJECTIVE: We examined differences in change from baseline to 1-, 2-, and 3-year follow-up in health-related quality of life and symptom severity among patients who underwent abdominal myomectomy, laparoscopic or robotic myomectomy, abdominal hysterectomy, laparoscopic or robotic hysterectomy, or uterine artery embolization. STUDY DESIGN: The COMPARE-UF registry is a multiinstitutional prospective observational cohort study of women undergoing treatment for uterine fibroids. A subset of 1384 women aged 31 to 45 years who underwent either abdominal myomectomy (n=237), laparoscopic myomectomy (n=272), abdominal hysterectomy (n=177), laparoscopic hysterectomy (n=522), or uterine artery embolization (n=176) were included in this analysis. We obtained demographics, fibroid history, and symptoms by questionnaires at enrollment and at 1, 2, and 3 years posttreatment. We used the UFS-QoL (Uterine Fibroid Symptom and Quality of Life) questionnaire to ascertain symptom severity and health-related quality of life scores among participants. To account for potential baseline differences across treatment groups, a propensity score model was used to derive overlap weights and compare total health-related quality of life and symptom severity scores after enrollment with a repeated measures model. For this health-related quality of life tool, a specific minimal clinically important difference has not been determined, but on the basis of previous research, a difference of 10 points was considered as a reasonable estimate. Use of this difference was agreed upon by the Steering Committee at the time when the analysis was planned. RESULTS: At baseline, women undergoing hysterectomy and uterine artery embolization reported the lowest health-related quality of life scores and highest symptom severity scores compared with those undergoing abdominal myomectomy or laparoscopic myomectomy (P<.001). Those undergoing hysterectomy and uterine artery embolization reported the longest duration of fibroid symptoms with a mean of 6.3 years (standard deviation, 6.7; P<.001). The most common fibroid symptoms were menorrhagia (75.3%), bulk symptoms (74.2%), and bloating (73.2%). More than half (54.9%) of participants reported anemia, and 9.4% women reported a history of blood transfusion. Across all modalities, total health-related quality of life and symptom severity score markedly improved from baseline to 1-year with the largest improvement in the laparoscopic hysterectomy group (Uterine Fibroids Symptom and Quality of Life: delta= [+] 49.2; symptom severity: delta= [-] 51.3). Those undergoing abdominal myomectomy, laparoscopic myomectomy, and uterine artery embolization also demonstrated significant improvement in health-related quality of life (delta= [+]43.9, [+]32.9, [+]40.7, respectively) and symptom severity (delta= [-]41.4, [-] 31.5, [-] 38.5, respectively) at 1 year, and the improvement persisted from baseline for uterine-sparing procedures during second (Uterine Fibroids Symptom and Quality of Life: delta= [+]40.7, [+]37.4, [+]39.3 SS: delta= [-] 38.5, [-] 32.0, [-] 37.7 and third year (Uterine Fibroids Symptom and Quality of Life: delta= [+] 40.9, [+]39.9, [+]41.1 and SS: delta= [-] 33.9, [-]36.5, [-] 33.0, respectively), posttreatment intervals, however with a trend toward decline in degree of improvement from years 1 and 2. Differences from baseline were greatest for hysterectomy; however, this may reflect the relative importance of bleeding in the Uterine Fibroids Symptom and Quality of Life, rather than clinically meaningful symptom recurrence among women undergoing uterus-sparing treatments. CONCLUSION: All treatment modalities were associated with significant improvements in health-related quality of life and symptom severity reduction 1-year posttreatment. However, abdominal myomectomy, laparoscopic myomectomy and uterine artery embolization indicated a gradual decline in symptom improvement and health-related quality of life by third year after the procedure.

New treatment options for nonsurgical management of uterine fibroids.

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.

Hysterectomy With and Without Oophorectomy, Tubal Ligation, and Risk of Cardiovascular Disease in the Nurses' Health Study II.

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.

Oral Gonadotropin-Releasing Hormone Antagonists for the Treatment of Uterine Leiomyomas.

Uterine leiomyomas are common hormone-responsive neoplasms that frequently cause heavy menstrual bleeding, anemia, pelvic pressure, pain, and adverse reproductive outcomes. In this overview, the efficacy and safety of oral gonadotropin-releasing hormone (GnRH) antagonists, co-administered with menopausal replacement-level steroid hormones or used at doses to avoid complete hypothalamic suppression, are reviewed for the management of uterine leiomyomas. Oral GnRH antagonists provide rapid suppression of sex steroids and avoid the initial steroidal flare and resultant temporary worsening of symptoms typically seen with parenteral GnRH agonists. Oral GnRH antagonists are effective in reducing leiomyoma-associated heavy menstrual bleeding, with high rates of amenorrhea and improved anemia and leiomyoma-associated pain, and providing modest reduction in uterine volume when used in combination with menopausal replacement-level steroid hormones. This add-back therapy can reduce hypogonadal side effects, including hot flushes and bone mineral density loss, close to levels seen with placebo therapy. Currently, both elagolix 300 mg twice daily with once-daily estradiol (1 mg) and norethindrone (0.5 mg) and relugolix 40 mg once daily with estradiol (1 mg) and norethindrone (0.5 mg) combination therapy are approved for leiomyoma treatment by the U.S. Food and Drug Administration. Linzagolix is under investigation in the United States but approved at two does with and without steroid hormones in the European Union. The efficacy of these agents appears to be robust over a wide spectrum of clinical presentations, demonstrating that worse disease parameters at baseline do not appear to inhibit efficacy. Across clinical trials, participants largely reflected the population of individuals affected by uterine leiomyomas.

Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis.

Objective: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment. Methods: Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded in vitro and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue® Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures. Results: Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis in vitro. Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment. Conclusion: Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis in vivo and in vitro. Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways.