Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

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

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.

Spontaneous regression of a giant uterine leiomyoma after delivery: a case report and literature review.

BACKGROUND: Uterine leiomyomas are hormone-dependent benign tumors and often begin to shrink after menopause due to the reduction in ovarian steroids. The influence of pregnancy on uterine leiomyomas size remains unclear. Here, we present a case of spontaneous regression of a giant uterine leiomyoma after delivery. CASE PRESENTATION: A 40-year-old woman presented with multiple uterine leiomyomas, one of which is a giant uterine leiomyomas (approximately 8 cm in diameter) that gradually shrinked after delivery. At over two months postpartum, the large myometrial leiomyoma had transformed into a submucosal leiomyoma, and over 3 years postpartum, both the submucosal leiomyoma and multiple intramural leiomyomas completely regressed. CONCLUSION: Spontaneous regression of a giant uterine leiomyom is rare after delivery. Considering uterine leiomyoma regression until over 3 year postpartum,we need to observe the regression of uterine fibroid for a longer time postpartum in the absence of fibroid related complications. In addition, it will provide new insights for treatment options of uterine leiomyomas in the future.

The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis.

OBJECTIVE: The objective of the meta-analysis was to determine the influence of uterine fibroids on adverse outcomes, with specific emphasis on multiple or large (≥ 5 cm in diameter) fibroids. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), and SinoMed databases for eligible studies that investigated the influence of uterine fibroids on adverse outcomes in pregnancy. The pooled risk ratio (RR) of the variables was estimated with fixed effect or random effect models. RESULTS: Twenty-four studies with 237 509 participants were included. The pooled results showed that fibroids elevated the risk of adverse outcomes, including preterm birth, cesarean delivery, placenta previa, miscarriage, preterm premature rupture of membranes (PPROM), placental abruption, postpartum hemorrhage (PPH), fetal distress, malposition, intrauterine fetal death, low birth weight, breech presentation, and preeclampsia. However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia. Subgroup analysis showed an association between larger fibroids and significantly elevated risks of breech presentation, PPH, and placenta previa in comparison with small fibroids. Multiple fibroids did not increase the risk of breech presentation, placental abruption, cesarean delivery, PPH, placenta previa, PPROM, preterm birth, and intrauterine growth restriction. Meta-regression analyses indicated that maternal age only affected the relationship between uterine fibroids and preterm birth, and BMI influenced the relationship between uterine fibroids and intrauterine fetal death. Other potential confounding factors had no impact on malposition, fetal distress, PPROM, miscarriage, placenta previa, placental abruption, and PPH. CONCLUSION: The presence of uterine fibroids poses increased risks of adverse pregnancy and obstetric outcomes. Fibroid size influenced the risk of breech presentation, PPH, and placenta previa, while fibroid numbers had no impact on the risk of these outcomes.

Mullerian adenosarcoma of the uterus with MASO: a case report of cervical adenosarcoma in a young female that never had sexual behavior.

BACKGROUND: Cervical mullerian adenosarcoma is a rare uterine sarcoma, especially in young women. Its pathological features are low-grade malignant tumors with bidirectional differentiation, and the degree of malignancy is similar to that of low-grade endometrial stromal sarcoma. This paper reports the case of a young asexual patient who has been closely followed up after tumor resection and has not had any recurrences. CASE PRESENTATION: A 20-year-old, young asexual woman was diagnosed with cervical mullerian adenosarcoma with sarcomatous overgrowth (MASO). Cervical tumor resection was performed after admission, and the resection margin was negative. After the operation, she refused to undergo secondary surgery due to fertility requirements and did not receive adjuvant treatment. The patient was closely followed up after the operation and has not yet relapsed. CONCLUSION: A young woman with cervical MASO did not receive adjuvant treatment after cervical tumor resection. For women with fertility requirements, close follow-ups should be conducted after the operation to guard against tumor recurrence and radical tumor resection should be performed as early as possible after the patient no longer requires their fertility.

Pseudo-Meigs syndrome caused by a rapidly enlarging hydropic leiomyoma with elevated CA125 levels mimicking ovarian malignancy: a case report and literature review.

Pseudo-Meigs syndrome is a rare syndrome characterized by hydrothorax and ascites associated with pelvic masses, and patients occasionally present with elevated serum cancer antigen-125 (CA125) levels. Hydropic leiomyoma (HLM) is an uncommon subtype of uterine leiomyoma characterized by hydropic degeneration and secondary cystic changes. Rapidly enlarging HLMs accompanied by hydrothorax, ascites, and elevated CA125 levels may be misdiagnosed as malignant tumors. Here, we report a case of HLM in a 45-year-old Chinese woman who presented with ascites and hydrothorax. Preoperative abdominopelvic CT revealed a giant solid mass in the fundus uteri measuring 20 × 15 × 12 cm. Her serum CA125 level was elevated to 247.7 U/ml, while her hydrothorax CA125 level was 304.60 U/ml. The patient was initially diagnosed with uterine malignancy and underwent total abdominal hysterectomy and adhesiolysis. Pathological examination confirmed the presence of a uterine hydropic leiomyoma with cystic changes. After tumor removal, the ascites and hydrothorax subsided quickly, with no evidence of recurrence. The patient's serum CA125 level decreased to 116.90 U/mL on Day 7 and 5.6 U/mL on Day 40 postsurgery. Follow-up data were obtained at 6 months, 1 year, and 2 years after surgery, and no recurrence of ascites or hydrothorax was observed. This case highlights the importance of accurate diagnosis and appropriate management of HLM to achieve successful outcomes.

Pulmonary benign metastasizing leiomyoma presenting as acute hypoxemic respiratory failure: a case report.

Pulmonary benign metastasizing leiomyoma is an uncommon condition, predominantly affecting women of childbearing age with a history of uterine smooth muscle tumors and uterine leiomyoma surgery for uterine leiomyoma. The progression of PBML is often unpredictable and depends on the extent of lung involvement. Generally, most patients remain asymptomatic, but a minority may experience coughing, wheezing, or shortness of breath, which are frequently misdiagnosed as pneumonia. consequently, this presents significant challenges in both treatment and nursing care before diagnosis. This paper reports the case of a 35-year-old woman primarily diagnosed with acute hypoxic respiratory failure who was transferred from the emergency room to the intensive care unit. The initial computed tomography scan of the patient's lungs indicated diffuse interstitial pneumonia, but the sequencing of the alveolar lavage fluid pathogen macro did not detect any bacteria, fungi, or viruses. Moreover, the patient remained in a persistent hypoxic state before the definitive diagnosis. Therefore, our focus was on maintaining the airway patency of the patient, using prone ventilation, inhaling nitric oxide, monitoring electrical impedance tomography, and preventing ventilator-associated pneumonia to improve oxygenation, while awaiting immunohistochemical staining of the patient's biopsied lung tissue. This would help us clarify the diagnosis and treat it based on etiology. After meticulous treatment and nursing care, the patient was weaned off the ventilator after 26 days and transferred to the respiratory ward after 40 days. This case study may serve as a reference for clinical practice and assist patients suffering from PBML.

Perioperative Venous Thromboembolism Risk in Patients Undergoing Hysterectomy for Fibroids: A US Retrospective Cohort Study.

OBJECTIVES: Venous thromboembolism (VTE) occurs in 0.4%-0.7% of benign hysterectomies. Pelvic vascular compression secondary to fibroids may elevate VTE risk. We aimed to evaluate the incidence and timing of VTE among individuals undergoing hysterectomy for fibroids and other benign indications. METHODS: Retrospective cohort study of patients who underwent a hysterectomy for fibroid and non-fibroid indications from January 2015 to December 2021. Main outcome measure was VTE consisting of pulmonary embolism or deep venous thrombosis diagnosed during 3 periods: (1) preoperative (1 year before surgery until day before surgery), (2) early postoperative (surgery date through 6 weeks after surgery), and (3) late postoperative (6 weeks to 1 year after surgery). Demographics, comorbidities, surgical characteristics, and VTE rates were compared by indication. RESULTS: A total of 263 844 individuals with fibroids and 203 183 without were identified. In total, 1.1% experienced VTE. On multivariable regression (adjusted demographic confounders and route of surgery), the presence of fibroids was associated with increased odds of preoperative (adjusted odds ratio [aOR] 1.12; 95% CI 1.03-1.22, P = 0.011) and reduced odds of late postoperative VTE (aOR 0.81; 95% CI 0.73-0.91, P < 0.001). For individuals with fibroids, uterine weight ≥250 g and undergoing laparotomy were independently associated with preoperative (aOR 1.29; 95% CI 1.09-1.52, P = 0.003 and aOR 2.32; 95% CI 2.10-2.56, P < 0.001) and early postoperative VTE (aOR 1.32; 95% CI 1.08-1.62, P = 0.006 and aOR 1.72; 95% CI 1.50-1.96, P < 0.001). CONCLUSIONS: Patients with fibroids were at increased odds of having VTE 1 year before hysterectomy. For those with fibroids, elevated uterine weight and laparotomy were associated with greater risk of preoperative and early postoperative VTEs.

Perioperative and reproductive outcomes' comparison of mini-laparotomy and laparoscopic myomectomy in the management of uterine leiomyomas: a systematic review.

OBJECTIVE: To evaluate and compare mini-laparotomy (MLPT) with laparoscopic (LPS) myomectomy perioperative and reproductive outcomes. METHODS: We systematically searched for related articles in the MEDLINE, Embase, Web of Science and the Cochrane library databases. Nine studies (4 randomized, 3 retrospective, 1 prospective and 1 case-control study) which involved 1723 patients met the inclusion criteria and were considered eligible for inclusion. RESULTS: Demographic characteristics were similar between the two groups. LPS was associated with shorter hospital stay (p = 0.04), lower blood loss (p < 0.00001), shorter duration of median ileus (p < 0.00001) and fewer episodes of postoperative fever (p = 0.04). None of the reproductive factors examined (pregnancy rate, preterm delivery, vaginal delivery and delivery with caesarean section) in women diagnosed with unexplained infertility and/or symptomatic leiomyomas reached statistical significance although the results represent a small size effect. CONCLUSION: Our analysis demonstrated that LPS seems to be an alternative, safe and reliable surgical procedure for uterine leiomyoma treatment and in everyday practice seems to offer improved outcomes-regarding at least the perioperative period-over MLPT.

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

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

Modifiable prognostic factors in uterine fibroid development: a systematic review of literature.

BACKGROUND: Many risk factors in uterine fibroid development have been identified, but women and their physicians are less aware of the influence of lifestyle on uterine fibroid development. The objective of this systematic review is to investigate and summarize modifiable prognostic factors associated with uterine fibroid development. METHODS: Pubmed and Embase were searched for relevant articles according to PRISMA guidelines. References from included articles were screened and when relevant also included. Human in vivo studies on modifiable factors in fibroid development were included. Studies on non-modifiable factors and treatment, in vitro studies and animal studies were excluded. 607 articles were screened and 33 articles were included. Two independent investigators collected data from the report. RESULTS: The strongest risk factor for fibroid development was a high BMI, while the strongest protective factors were a high fruit and vegetable intake and high vitamin D intake. CONCLUSION: More high-quality studies are necessary to better understand the impact of the abovementioned factors as well as the role they play in the growth of already existing fibroids.

Uterine fibroid development is multifactorial. Various non-modifiable and modifiable factors have been linked to uterine fibroid development. Modifiable factors are controllable by patients themselves. We performed a systematic review to investigate these modifiable factors. We screened 607 articles from 2 databases (PubMed and Embase) of which 33 were included in the review. We only included clinical studies on humans. A high body mass index (BMI) is found to be a modifiable risk factor for uterine fibroid development. Protective of uterine fibroid development are high fruit and vegetable intake and high vitamin D intake or sun exposure. More research is needed to investigate the applicability of these findings in clinical practice and to investigate the influence on the growth of already existing uterine fibroids.

Metrics of uterine myomatosis symptomatology in clinical practice.

AIM: A review of diagnostic options and standardized methods for specifying clinical symptoms associated with uterine myomatosis. METHODS: A literature search of databases aimed at finding validated metrics for assessing myomas symptomatology. RESULTS: Summary of obligatory and optional examination methods in the diagnosis of uterine fibroids and methods of examination of reproductive parameters of the couple in relation to myomatosis. Defining the metrics of bleeding manifestations of myomatosis with emphasis on the "Pictorial Bleeding Assessment Chart". Reviewing metrics of algic manifestations of myomatosis and quality of life with emphasis on the "Quality of Life Questionnaire - Myomatosis - Severity Symptom Scale". CONCLUSION: The purpose of the applicable metrics, which summarize objective findings and subjective complaints of patients, is to describe and evaluate possible correlations and dynamics of changes in the health status, depending on the chosen therapy.

Currently Available Treatment Modalities for Uterine Fibroids.

Uterine fibroids (leiomyomas and myomas) are the most common benign gynecological condition in patients presenting with abnormal uterine bleeding, pelvic masses causing pressure or pain, infertility and obstetric complications. Almost a third of women with fibroids need treatment due to symptoms. OBJECTIVES: In this review we present all currently available treatment modalities for uterine fibroids. METHODS: An extensive search for the available data regarding surgical, medical and other treatment options for uterine fibroids was conducted. REVIEW: Nowadays, treatment for fibroids is intended to control symptoms while preserving future fertility. The choice of treatment depends on the patient's age and fertility and the number, size and location of the fibroids. Current management strategies mainly involve surgical interventions (hysterectomy and myomectomy hysteroscopy, laparoscopy or laparotomy). Other surgical and non-surgical minimally invasive techniques include interventions performed under radiologic or ultrasound guidance (uterine artery embolization and occlusion, myolysis, magnetic resonance-guided focused ultrasound surgery, radiofrequency ablation of fibroids and endometrial ablation). Medical treatment options for fibroids are still restricted and available medications (progestogens, combined oral contraceptives andgonadotropin-releasing hormone agonists and antagonists) are generally used for short-term treatment of fibroid-induced bleeding. Recently, it was shown that SPRMs could be administered intermittently long-term with good results on bleeding and fibroid size reduction. Novel medical treatments are still under investigation but with promising results. CONCLUSIONS: Treatment of fibroids must be individualized based on the presence and severity of symptoms and the patient's desire for definitive treatment or fertility preservation.

Can MRI Accurately Diagnose and Stage Endometrial Adenocarcinoma?

Background and Objectives: Endometrial carcinoma is one of the most common gynecological cancers, and benign lesions such as endometrial hyperplasia, polyps, adenomyosis and leiomyomas should be included in the differential diagnosis. Magnetic resonance imaging has an important role in evaluating endometrial cancer and assessing the depth of myometrial invasion, and it closely correlates with the prognosis of the patient. The purpose of this study is to evaluate the MRI semiology of the endometrial carcinomas that mimic benign lesions, the main factors that may affect the correct diagnosis and the feasibility of magnetic resonance imaging to evaluate the depth of the myometrial invasion of endometrial cancer. Materials and Methods: This is a retrospective analysis of 45 patients that underwent MRI examinations and the lesions were pathologically diagnosed as endometrial carcinoma after surgical resection. This study evaluated the staging accuracy of T2-weighted imaging, diffusion-weighted imaging (DWI), ADC mapping and T1-weighted imaging with fat saturation before and after gadolinium injection. Results: In 36 of the 45 cases, the MRI of the lesion showed the characteristics of endometrial cancer and the diagnosis was certain. Nine lesions (20%) were described as unequivocal and had unspecific MR appearance. In eight of the nine cases (89%), the histopathologic report revealed the presence of leiomyomas and two of these cases (22%) were also associated with adenomyosis. The cause of underestimation in these patients was coexisting lesions exhibiting heterogenous intensity and contrast enhancement, which made it difficult to detect the margins of the lesions. The depth of the myometrial invasion was underestimated in nine cases and overestimated in three cases. The staging accuracy with MRI was 74%. There was a significant correlation between MR imaging and histopathologic finding in the assessment of myometrial invasion (p < 0.001). Cervical extension was noted in eight cases (18%), but was missed on MR imaging in two patients and overstaged in none. Six of them were associated with myometrial invasion in more than 50% of the thickness. There was a significant correlation between MR imaging and histopathologic finding in the assessment of cervical extension (p < 0.001). Conclusions: Our data confirm the high accuracy of MRI in the diagnosis and local staging of endometrial carcinoma. The information provided by MRI has an important role in planning the treatment and the prognosis of the patients.

Procedural sedation and analgesia versus general anesthesia for hysteroscopic myomectomy (PROSECCO trial): A multicenter randomized controlled trial.

BACKGROUND: Hysteroscopic resection is the first-choice treatment for symptomatic type 0 and 1 fibroids. Traditionally, this was performed under general anesthesia. Over the last decade, surgical procedures are increasingly being performed in an outpatient setting under procedural sedation and analgesia. However, studies evaluating safety and effectiveness of hysteroscopic myomectomy under procedural sedation are lacking. This study aims to investigate whether hysteroscopic myomectomy under procedural sedation and analgesia with propofol is noninferior to hysteroscopic myomectomy under general anesthesia. METHODS AND FINDINGS: This was a multicenter, randomized controlled noninferiority trial conducted in 14 university and teaching hospitals in the Netherlands between 2016 and 2021. Inclusion criteria were age ≥18 years, maximum number of 3 type 0 or 1 fibroids, maximum fibroid diameter 3.5 cm, American Society of Anesthesiologists class 1 or 2, and having sufficient knowledge of the Dutch or English language. Women with clotting disorders or with severe anemia (Hb < 5.0 mmol/L) were excluded. Women were randomized using block randomization with variable block sizes of 2, 4, and 6, between hysteroscopic myomectomy under procedural sedation and analgesia (PSA) with propofol or under general anesthesia (GA). Primary outcome was the percentage of complete resections, assessed on transvaginal ultrasonography 6 weeks postoperatively by a sonographer blinded for the treatment arm and surgical outcome. Secondary outcomes were the surgeon's judgment of completeness of procedure, menstrual blood loss, uterine fibroid related and general quality of life, pain, recovery, hospitalization, complications, and surgical reinterventions. Follow-up period was 1 year. The risk difference between both treatment arms was estimated, and a Farrington-Manning test was used to determine the p-value for noninferiority (noninferiority margin 7.5% of incomplete resections). Data were analyzed according to the intention-to-treat principle, including a per-protocol analysis for the primary outcome. A total of 209 women participated in the study and underwent hysteroscopic myomectomy with PSA (n = 106) or GA (n = 103). Mean age was 45.1 [SD 6.4] years in the PSA group versus 45.0 [7.7] years in the GA group. For 98/106 women in the PSA group and 89/103 women in the GA group, data were available for analysis of the primary outcome. Hysteroscopic resection was complete in 86/98 women (87.8%) in the PSA group and 79/89 women (88.8%) in the GA group (risk difference -1.01%; 95% confidence interval (CI) -10.36 to 8.34; noninferiority, P = 0.09). No serious anesthesiologic complications occurred, and conversion from PSA to GA was not required. During the follow-up period, 15 serious adverse events occurred (overnight admissions). All were unrelated to the intervention studied. Main limitations were the choice of primary outcome and the fact that our study proved to be underpowered. CONCLUSIONS: Noninferiority of PSA for completeness of resection was not shown, though there were no significant differences in clinical outcomes and quality of life. In this study, hysteroscopic myomectomy for type 0 and 1 fibroids with PSA compared to GA was safe and led to shorter hospitalization. These results can be used for counseling patients by gynecologists and anesthesiologists. Based on these findings, we suggest that hysteroscopic myomectomies can be performed under PSA in an outpatient setting. TRIAL REGISTRATION: The study was registered prospectively in the Dutch Trial Register (NTR 5357; registration date: 11 August 2015; Date of initial participant enrollment: 18 February 2016).

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

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

Infertility in patients with uterine fibroids: a debate about the hypothetical mechanisms.

Fibroids are benign tumours of the myometrium and are the most common gynaecologic abnormality. Although most fibroids are asymptomatic, they can cause symptoms like heavy menstrual bleeding, pelvic pain, sexual dysfunction, pressure complaints, and infertility. The association between fibroids and infertility has been debated for decades. It is generally acknowledged that the closer the fibroid is to the uterine cavity and the endometrium lining, the more unfavourable effect it might have on fertility, reducing the odds for successful implantation and gestation. Based on the limited available literature, we propose and discuss seven hypotheses on the underlying mechanism by which fibroids may reduce fertility. (i) Fibroids can cause sexual dysfunction, as fibroids can cause dyspareunia, pelvic pain, and prolonged and heavy menstrual bleeding, which could interfere with sexual arousal and as a consequence the frequency of intercourse, resulting in a reduced probability of conception. (ii) Mechanical compression by fibroids on theinterstitial part of the fallopian tubes or deformation of uterine cavity could disturb oocyte and sperm transport. (iii) Fibroids can disturb peristalsis of the junctional zone in the myometrium, which could negatively influence oocyte and sperm transport as well as implantation. In addition, fibroids could induce a detrimental environment for implantation in other ways, by: (iv) changing the vagino-uterine microbiome; (v) disturbing the levels of inflammation and autophagy; (vi) inducing molecular changes in the endometrium; and (vii) inducing aberrant angiogenesis and altering the endometrial blood supply. After the discussion of these hypotheses, the implication of the influence of fibroids on early pregnancy loss is discussed. Surgical fibroid treatment is not tailored nor focussed on the pathophysiology of the fibroid; consequently it may be accompanied by recurrence of fibroids and risks of complications. Unravelling the pathogenic mechanisms about how fibroids influence fertility is essential to evolve classic surgical fibroid treatment. Instead of treatment of fibroid-related symptoms, the research should supports development of fibroid-targeted (pharmaceutical) treatment that is compatible with an active wish to become pregnant.

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

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

A prospective ultrasound study of cigarette smoking and uterine leiomyomata incidence and growth.

BACKGROUND: Uterine leiomyomata (fibroids) are common, benign neoplasms that contribute substantially to gynecologic morbidity. Some existing epidemiologic studies indicate that cigarette smoking is associated with lower uterine leiomyomata risk. However, no prospective studies have systematically screened an entire study population for uterine leiomyomata using transvaginal ultrasound or evaluated the association between cigarette smoking and uterine leiomyomata growth. OBJECTIVE: This study aimed to examine the association between cigarette smoking and uterine leiomyomata incidence and growth in a prospective ultrasound study. STUDY DESIGN: We enrolled 1693 residents from the Detroit metropolitan area into the Study of Environment, Lifestyle, and Fibroids during 2010 to 2012. Eligible participants were aged 23 to 34 years, had an intact uterus but no previous diagnosis of uterine leiomyomata, and self-identified as Black or African American. We invited participants to complete a baseline visit and 4 follow-up visits over approximately 10 years. At each visit, we used transvaginal ultrasound to assess uterine leiomyomata incidence and growth. Participants provided extensive self-reported data throughout follow-up including exposures to active and passive cigarette smoking in adulthood. We excluded participants who did not return for any follow-up visits (n=76; 4%). We fit Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals for the association between time-varying smoking history and incidence rates of uterine leiomyomata. We fit linear mixed models to estimate the percentage difference and 95% confidence intervals for the association between smoking history and uterine leiomyomata growth. We adjusted for sociodemographic, lifestyle, and reproductive factors. We interpreted our results based on magnitude and precision rather than binary significance testing. RESULTS: Among 1252 participants without ultrasound evidence of uterine leiomyomata at baseline, uterine leiomyomata were detected in 394 participants (31%) during follow-up. Current cigarette smoking was associated with a lower uterine leiomyomata incidence rate (hazard ratio, 0.67; 95% confidence interval, 0.49-0.92). Associations were stronger among participants who had smoked for longer durations (≥15 years vs never: hazard ratio, 0.49; 95% confidence interval, 0.25-0.95). The hazard ratio for former smokers was 0.78 (95% confidence interval, 0.50-1.20). Among never smokers, the hazard ratio for current passive smoke exposure was 0.84 (95% confidence interval, 0.65-1.07). Uterine leiomyomata growth was not appreciably associated with current (percent difference, -3%; 95% confidence interval, -13% to 8%) or former (percent difference, -9%; 95% confidence interval, -22% to 6%) smoking. CONCLUSION: We provide evidence from a prospective ultrasound study that cigarette smoking is associated with lower uterine leiomyomata incidence.

Postoperative venous thromboembolism risk stratification in patients with uterine cancer.

BACKGROUND: Uterine cancers are associated with a high risk for venous thromboembolisms. The American Society of Clinical Oncology practice guidelines recommend that all patients undergoing pelvic surgery for cancer should receive extended pharmacologic thromboprophylaxis with the duration being dependent on risk. However, risk stratification for patients with uterine cancer is not clearly defined. The Caprini score is the most widely used risk assessment model but it has been found to have limited use in the gynecologic oncology population. A modified Caprini score has been explored in other populations. The Khorana score is an additional risk assessment model that has not been studied in this context. OBJECTIVE: Our objective was to evaluate the ability of a modified Caprini model and the Khorana score to risk stratify patients with uterine cancer for postoperative venous thromboembolisms within 90 days of surgery. STUDY DESIGN: Following institutional review board approval, a retrospective cohort study was performed, and all patients with uterine cancer who underwent a hysterectomy over a 4-year period were included. The Caprini and Khorana scores were calculated for each patient. The Caprini score cutoff for highest risk was evaluated at ≥7, ≥8, and ≥9 (modified Caprini) and the Khorana score cutoff was evaluated at ≥2 and ≥3. To determine the prognostic use of each score and other clinico-pathologic criteria related to the development of a venous thromboembolism, univariate analyses were performed using independent t tests, chi-square tests, or Fisher's exact tests; a multivariate analysis was performed using logistic regression. RESULTS: A total of 954 patients were included. The rate of venous thromboembolism development was 1.7% (16/954). A minimally invasive surgical approach was used in 90.5% (863/954) of patients. The mean Caprini score for patients with a venous thromboembolism was 10.3 compared with 8.1 for patients without a venous thromboembolism (95% confidence interval, 1.17-3.33; P<.0001). The mean Khorana score for the venous thromboembolism group was 2.4 vs 1.9 for those without (95% confidence interval, 0.04-0.82; P=.03). Both the Caprini and Khorana scores were found to be associated with venous thromboembolisms, but only a Caprini score with a cutoff of ≥8 or ≥9 was statistically significant (risk ratio, 31.25; 95% confidence interval, 1.88-519.49; risk ratio, 4.59; 95% confidence interval, 1.49-14.13, respectively), with high accuracy based on the area under the curve (0.75 and 0.68, respectively). Of the minimally invasive subgroup, 11.7% (101/863) of patients had same-day discharge with no postoperative thromboprophylaxis; none of these patients developed venous thromboembolisms. Despite extended prophylaxis among the laparotomy patients (30 days), the rate of venous thromboembolisms was more than 3 times that of the minimally invasive group (5.49% vs 1.7%). Advanced tumor stage and leukocytosis were noted to be independent risk factors for venous thromboembolisms. CONCLUSION: Our study suggests that using a modified Caprini score could help to identify the highest-risk patients who would benefit from prolonged thromboprophylaxis, could reduce the incidence of postoperative venous thromboembolisms, and could minimize the cost and harm of overtreatment. These findings need to be validated in a prospective manner, and further research is needed to determine the optimal duration of therapy.