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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.).
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Estradiol/administración & dosificación , Leiomioma/tratamiento farmacológico , Menorragia/tratamiento farmacológico , Acetato de Noretindrona/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Pirimidinonas/administración & dosificación , Neoplasias Uterinas/tratamiento farmacológico , Adulto , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Estrógenos/administración & dosificación , Femenino , Sofocos/inducido químicamente , Humanos , Leiomioma/complicaciones , Menorragia/etiología , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Pirimidinonas/efectos adversos , Neoplasias Uterinas/complicaciones , Adulto JovenRESUMEN
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.
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Leiomioma , Menorragia , Compuestos de Fenilurea , Pirimidinonas , Neoplasias Uterinas , Femenino , Humanos , Amenorrea , Negro o Afroamericano , Leiomioma/complicaciones , Leiomioma/tratamiento farmacológico , Menorragia/tratamiento farmacológico , Menorragia/etiología , Compuestos de Fenilurea/uso terapéutico , Pirimidinonas/uso terapéutico , Calidad de Vida , Neoplasias Uterinas/complicaciones , Adolescente , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive. OBJECTIVE: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women. STUDY DESIGN: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16). RESULTS: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women. CONCLUSION: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.
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BACKGROUND: Primary ovarian insufficiency refers to the loss of ovarian function before the age of 40 years and leads to amenorrhea and infertility. Primary ovarian insufficiency has diverse causes, but a common cause is exposure to gonadotoxic chemotherapy used in cancer treatment. Because of the risk for developing primary ovarian insufficiency, patients who want to preserve their fertility may consider various procedures for fertility preservation. However, current fertility preservation options are highly invasive, carry substantial risks, and have uncertain success rates. Recent studies from our group and others reported that mesenchymal stem cells and mesenchymal stem cell-derived exosomes can restore ovarian function in preclinical models of primary ovarian insufficiency by restoring damaged cells and inhibiting apoptosis. Although the restorative effect of mesenchymal stem cell-derived exosomes has been well reported in previous studies, the potential of mesenchymal stem cell-derived exosomes in preventing ovarian damage has not been fully elucidated. OBJECTIVE: This study hypothesized that the antiapoptotic potential of mesenchymal stem cell-derived exosomes may protect ovarian tissue from chemotherapy-induced damage. STUDY DESIGN: In this study, we delivered mesenchymal stem cell-derived exosomes directly into the ovaries of mice before administration of chemotherapy. A total of 60 mice were divided into 3 groups (20 per group), which were labeled the control, chemotherapy, and fertility protection groups. Only the fertility protection group mice received exosomes, whereas the control and chemotherapy group mice received saline. After exosome injection, the chemotherapy and fertility protection groups of mice were subjected to chemotherapy to induce ovarian damage. After chemotherapy, we evaluated the protective effects of exosome treatment on ovarian function, such as estrous cyclicity, serum hormone levels, and the fertility rate, by comparing these outcomes between the chemotherapy and fertility protection groups. These outcomes were also compared with those of the control group for comparison with outcomes under healthy conditions. RESULTS: After intraovarian injection of exosomes before chemotherapy, the mice were able to maintain their estrous cycle (4- to 5-day cyclicity), serum anti-müllerian hormone level (66.06±26.40 ng/mL, not significantly different from that of the healthy controls), folliculogenesis (32.2±11.3 in the chemotherapy group vs 46.4±14.1 in the fertility protection group; P<.05), expression of the steroidogenic acute regulatory protein gene (a the steroidogenesis marker) (0.44±0.11-fold expression in the chemotherapy group and 0.88±0.31-fold expression in the fertility protection group; P<.05), and fertility (2 of 8 in the chemotherapy group and 5 of 8 in the fertility protection group), thereby showing prevention of chemotherapy-induced damage. We found that exosome treatment before chemotherapy can preserve ovarian function and protect fertility through the overexpression of ATP synthase-binding cassette transporters, such as ABCB1b (10.17±17.75-fold expression in the chemotherapy group and 44.14±33.25-fold expression in the fertility protection group; P<.05) and ABCC10 (3.25±0.59-fold expression in the chemotherapy group and 5.36±1.86-fold expression in the fertility protection group; P<.05). CONCLUSION: In this study, we present a novel fertility protection method using mesenchymal stem cell-derived exosomes. We concluded that mesenchymal stem cell-derived exosomes are a promising and simple treatment option for fertility protection in reproductive-aged patients who are receiving gonadotoxic chemotherapy.
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Exosomas , Preservación de la Fertilidad , Células Madre Mesenquimatosas , Ovario , Insuficiencia Ovárica Primaria , Femenino , Animales , Exosomas/metabolismo , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/prevención & control , Insuficiencia Ovárica Primaria/terapia , Preservación de la Fertilidad/métodos , Ratones , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ovario/efectos de los fármacos , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Hormona Antimülleriana/metabolismo , Hormona Antimülleriana/sangreRESUMEN
BACKGROUND: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients. OBJECTIVE: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women. STUDY DESIGN: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses. RESULTS: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetracoidpeptide repeat protein 38. CONCLUSION: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations.
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BACKGROUND: The stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the epigenome and increases the risk of hormone-related illnesses like uterine fibroids (UFs). METHODS: Developmental reprogramming of myometrial stem cells (MMSCs), the putative origin from which UFs originate, was investigated in vitro and in the Eker rat model by RNA-seq, ChIP-seq, RRBS, gain/loss of function analysis, and luciferase activity assays. RESULTS: When exposed to the endocrine-disrupting chemical (EDC) diethylstilbestrol during Eker rat development, MMSCs undergo a reprogramming of their estrogen-responsive transcriptome. The reprogrammed genes in MMSCs are known as estrogen-responsive genes (ERGs) and are activated by mixed lineage leukemia protein-1 (MLL1) and DNA hypo-methylation mechanisms. Additionally, we observed a notable elevation in the expression of ERGs in MMSCs from Eker rats exposed to natural steroids after developmental exposure to EDC, thereby augmenting estrogen activity. CONCLUSION: Our studies identify epigenetic mechanisms of MLL1/DNA hypo-methylation-mediated MMSC reprogramming. EDC exposure epigenetically targets MMSCs and leads to persistent changes in the expression of a subset of ERGs, imparting a hormonal imprint on the ERGs, resulting in a "hyper-estrogenic" phenotype, and increasing the hormone-dependent risk of UFs.
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Disruptores Endocrinos , Leiomioma , Animales , Ratas , Disruptores Endocrinos/toxicidad , Estrógenos , Bioensayo , Leiomioma/inducido químicamente , Leiomioma/genética , Proteína de la Leucemia Mieloide-Linfoide , ADNRESUMEN
Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.
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Disruptores Endocrinos , Leiomioma , Femenino , Animales , Ratas , Reparación del ADN/genética , Daño del ADN , Factor de Crecimiento Transformador beta/genética , Carcinogénesis , Disruptores Endocrinos/toxicidad , Leiomioma/inducido químicamente , Leiomioma/genéticaRESUMEN
BACKGROUND: Uterine fibroids are benign monoclonal tumors originating from the smooth muscle cells of the myometrium, constituting the most prevalent pathology within the female genital tract. Uterine sarcomas, although rare, still represent a diagnostic challenge and should be managed in centers with adequate expertise in gynecological oncology. OBJECTIVES: This article is aimed to summarize and discuss cutting-edge elements about the diagnosis and management of uterine fibroids and sarcomas. METHODS: This paper is a report of the lectures presented in an expert meeting about uterine fibroids and sarcomas held in Palermo in February 2023. OUTCOME: Overall, the combination of novel molecular pathways may help combine biomarkers and expert ultrasound for the differential diagnosis of uterine fibroids and sarcomas. On the one hand, molecular and cellular maps of uterine fibroids and matched myometrium may enhance our understanding of tumor development compared to histologic analysis and whole tissue transcriptomics, and support the development of minimally invasive treatment strategies; on the other hand, ultrasound imaging allows in most of the cases a proper mapping the fibroids and to differentiate between benign and malignant lesions, which need appropriate management. CONCLUSIONS AND OUTLOOK: The choice of uterine fibroid management, including pharmacological approaches, surgical treatment, or other strategies, such as high-intensity focused ultrasound (HIFU), should be carefully considered, taking into account the characteristics of the patient and reproductive prognosis.
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Ultrasonido Enfocado de Alta Intensidad de Ablación , Leiomioma , Sarcoma , Miomectomía Uterina , Neoplasias Uterinas , Femenino , Humanos , Resultado del Tratamiento , Leiomioma/diagnóstico , Leiomioma/terapia , Leiomioma/patología , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Neoplasias Uterinas/patología , Pronóstico , Sarcoma/diagnóstico , Sarcoma/terapia , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodosRESUMEN
Perimenopause significantly impacts women's health globally, often managed with hormone replacement therapy (HRT) despite the associated risks. This study explores a novel alternative exosome therapy, aimed at stimulating estrogen production in ovarian tissues, thus offering a potential non-hormonal treatment for perimenopausal symptoms. Employing ex vivo methodologies, ovarian cortex specimens from perimenopausal women were treated with exosomes derived from human umbilical cord mesenchymal stem cells and cultured under specific conditions (patent number: PCT/US2022/073467). The exosomes were produced under cyclic guanosine monophosphate (cGMP) conditions, ensuring high safety standards. Estrogen levels were quantified using enzyme-linked immunosorbent assay (ELISA), and gene expression changes in estrogen and follicle-stimulating hormone (FSH) receptors were assessed via quantitative polymerase chain reaction (PCR). Immunohistochemistry (IHC) was utilized to evaluate cellular proliferation and apoptotic markers. The results indicated a significant increase in estrogen levels and estrogen receptor-alpha (Erα) expression in treated tissues compared to controls. Additionally, a decrease in apoptotic markers and an increase in cellular proliferation markers were observed. These findings suggest that exosome therapy can effectively enhance estrogen production and modulate receptor sensitivity in perimenopausal ovarian tissues. This approach could serve as a safer alternative to HRT, aligning with the body's natural regulatory mechanisms and potentially offering a more effective treatment option for managing perimenopausal symptoms.
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Estrógenos , Exosomas , Perimenopausia , Humanos , Exosomas/metabolismo , Femenino , Perimenopausia/metabolismo , Estrógenos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Proliferación Celular , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Persona de Mediana Edad , Apoptosis , Receptores de HFE/metabolismo , Receptores de HFE/genética , Ovario/metabolismoRESUMEN
Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.
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Epigenoma , Leiomioma , Humanos , Femenino , Epigénesis Genética , Proteínas que Contienen Bromodominio , Leiomioma/genética , Carcinogénesis/genética , Transformación Celular Neoplásica , Factores de Transcripción , Transducción de SeñalRESUMEN
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.
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Leiomioma , Menorragia , Neoplasias Uterinas , Ácidos Carboxílicos , Estradiol , Femenino , Humanos , Leiomioma/tratamiento farmacológico , Menorragia/complicaciones , Menorragia/etiología , Acetato de Noretindrona , Pirimidinas , Receptores LHRH/uso terapéutico , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/tratamiento farmacológicoRESUMEN
BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).
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Estradiol/uso terapéutico , Estrógenos/uso terapéutico , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hidrocarburos Fluorados/uso terapéutico , Leiomioma/complicaciones , Menorragia/tratamiento farmacológico , Pirimidinas/uso terapéutico , Adulto , Densidad Ósea/efectos de los fármacos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Sofocos/inducido químicamente , Humanos , Hidrocarburos Fluorados/efectos adversos , Menorragia/etiología , Persona de Mediana Edad , Pirimidinas/efectos adversos , Calidad de Vida , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
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.
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Leiomioma , Menorragia , Neoplasias Uterinas , Femenino , Humanos , Leiomioma/tratamiento farmacológico , Leiomioma/complicaciones , Menorragia/tratamiento farmacológico , Menorragia/etiología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/complicacionesRESUMEN
BACKGROUND: In the pivotal LIBERTY 1 and 2 trials and long-term extension study, once-daily relugolix combination therapy (40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) reduced menstrual blood loss volume and pain among women with uterine fibroids. Relugolix combination therapy was well tolerated with preservation of bone mineral density through 52 weeks. OBJECTIVE: This study aimed to report the 2-year relugolix combination therapy efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study. STUDY DESIGN: Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials, followed by the 28-week long-term extension study (up to 52 weeks total treatment), and who met the responder criteria (menstrual blood loss volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 [week 24 of long-term extension]) were randomized in a 1:1 ratio to either blinded treatment with relugolix combination therapy or placebo for 52 weeks (total treatment period, 104 weeks). For women who had a relapse of heavy menstrual bleeding during the study (menstrual blood loss volume ≥80 mL), open-label relugolix combination therapy was offered. The primary endpoint was the proportion of women who maintained menstrual blood loss volume <80 mL through week 76 (week 24 of randomized withdrawal study). Secondary endpoints included time to menstrual blood loss volume ≥80 mL, proportion of women who maintained a menstrual blood loss volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women who achieved or maintained amenorrhea at week 76 at the end of treatment, and the change in Uterine Fibroid Symptom-Quality of Life Bleeding and Pelvic Discomfort Scale and symptom severity scores. Analyses were performed for the modified intent-to-treat population, including all randomized women who received ≥1 dose of the study drug. RESULTS: Of the 229 randomized women (relugolix combination therapy, n=115; placebo, n=114), 228 received the study drug and 175 (76.7%) completed the randomized withdrawal study. Through week 76, 78.4% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 15.1% in the placebo group (difference, 63.4%; 95% confidence interval, 52.9%-73.9%; P<.0001). At week 104, 69.8% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 11.8% in the placebo group (difference, 58.0%; 95% confidence interval, 47.0%-69.1%; P<.0001). Through week 104, 88.3% of women on placebo relapsed with heavy menstrual bleeding (median time to relapse, 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix combination therapy with a menstrual blood loss volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference, 44.1%; 95% confidence interval, 33.10%-55.1%; P<.0001) and 58.3% vs 10.6% at week 104 (difference, 47.6%; 95% confidence interval, 37.0%-58.3%; nominal P<.0001) for relugolix combination therapy and the placebo group, respectively. Relugolix combination therapy was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density remained stable in women who received relugolix combination therapy from week 52 to week 104. In women continuously treated with relugolix combination therapy up to 2 years, bone mineral density was generally preserved. CONCLUSION: After 2 years of treatment with relugolix combination therapy, there was evidence of durability of the effect in maintaining low menstrual blood loss volume in women with symptomatic uterine fibroids. Most women had return of heavy menstrual bleeding and associated symptoms after treatment cessation, which improved upon retreatment with relugolix combination therapy. Relugolix combination therapy was well tolerated, the adverse event profile remained consistent, and the mean bone mineral density was generally preserved through 2 years of treatment.
Asunto(s)
Leiomioma , Menorragia , Neoplasias Uterinas , Femenino , Humanos , Menorragia/tratamiento farmacológico , Menorragia/etiología , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/tratamiento farmacológico , Amenorrea , Calidad de Vida , Recurrencia Local de Neoplasia , Leiomioma/complicaciones , Leiomioma/tratamiento farmacológico , Hemorragia Uterina/tratamiento farmacológico , Hemorragia Uterina/etiología , RecurrenciaRESUMEN
OBJECTIVE: To develop a core outcome set for heavy menstrual bleeding (HMB). DESIGN: Core outcome set (COS) development methodology described by the COMET initiative. SETTING: University hospital gynaecology department, online international survey and web-based international consensus meetings. POPULATION OR SAMPLE: An international collaboration of stakeholders (clinicians, patients, academics, guideline developers) from 20 countries and 6 continents. METHODS: Phase 1: Systematic review of previously reported outcomes to identify potential core outcomes. Phase 2: Qualitative studies with patients to identify outcomes most important to them. Phase 3: Online two-round Delphi survey to achieve consensus about which outcomes are most important. Phase 4: A consensus meeting to finalise the COS. MAIN OUTCOME MEASURES: Outcome importance was assessed in the Delphi survey on a 9-point scale. RESULTS: From the 'long list' of 114, 10 outcomes were included in the final COS: subjective blood loss; flooding; menstrual cycle metrics; severity of dysmenorrhoea; number of days with dysmenorrhoea; quality of life; adverse events; patient satisfaction; number of patients going on to have further treatment for HMB and haemoglobin level. CONCLUSIONS: The final COS includes variables that are feasible for use in clinical trials in all resource settings and apply to all known underlying causes of the symptom of HMB. These outcomes should be reported in all future trials of interventions, their systematic reviews, and clinical guidelines to underpin policy.
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Menorragia , Femenino , Humanos , Técnica Delphi , Dismenorrea , Menorragia/terapia , Evaluación de Resultado en la Atención de Salud/métodos , Calidad de Vida , Proyectos de Investigación , Resultado del Tratamiento , Ensayos Clínicos como AsuntoRESUMEN
Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. Although benign, UFs are associated with significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. A knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve UF patient outcomes. Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. This review summarizes the recent progress of ascertaining the biological functions and regulatory mechanisms in UFs, from the perspective of factors regulating ECM production, ECM-mediated signaling, and pharmacological drugs targeting ECM accumulation. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of the extracellular matrix in the pathogenesis of UFs and in applications. Comprehensive and deeper insights into ECM-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with this common tumor.
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Leiomioma , Neoplasias Uterinas , Recién Nacido , Femenino , Humanos , Neoplasias Uterinas/patología , Leiomioma/patología , Matriz Extracelular/patología , Transducción de Señal , Miometrio/patologíaRESUMEN
Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis and high rates of recurrence and metastasis. The origin and molecular mechanism underlying and driving its clinical and biological behavior remain largely unknown. Recently, we and others have revealed the role of microRNAs, DNA methylation, and histone modifications in contributing to the pathogenesis of uLMS. However, the connection between reversible m6A RNA methylation and uLMS pathogenesis remains unclear. In this study, we assessed the role and mechanism of FTO m6A RNA demethylase in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that the levels of RNA demethylases FTO and ALKBH5 were aberrantly upregulated in uLMS tissues compared to adjacent myometrium with a significant change by histochemical scoring assessment (p < 0.01). Furthermore, the inhibition of FTO demethylase with its small, potent inhibitor (Dac51) significantly decreased the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-seq analysis revealed that the inhibition of FTO with Dac51 exhibited a significant decrease in cell-cycle-related genes, including several CDK members, and a significant increase in the expression of CDKN1A, which correlated with a Dac51-exerted inhibitory effect on cell proliferation. Moreover, Dac51 treatment allowed the rewiring of several critical pathways, including TNFα signaling, KRAS signaling, inflammation response, G2M checkpoint, and C-Myc signaling, among others, leading to the suppression of the uLMS phenotype. Moreover, transcription factor (TF) analyses suggested that epitranscriptional alterations by Dac51 may alter the cell cycle-related gene expression via TF-driven pathways and epigenetic networks in uLMS cells. This intersection of RNA methylation and other epigenetic controls and pathways provides a framework to better understand uterine diseases, particularly uLMS pathogenesis with a dysregulation of RNA methylation machinery. Therefore, targeting the vulnerable epitranscriptome may provide an additional regulatory layer for a promising and novel strategy for treating patients with this aggressive uterine cancer.
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Leiomiosarcoma , MicroARNs , Neoplasias Pélvicas , Neoplasias Uterinas , Femenino , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Neoplasias Uterinas/patología , MicroARNs/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismoRESUMEN
The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a "hyper-inflammatory phenotype" and an increased hormone-dependent risk of UFs later in life.
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Leiomioma , Neoplasias Uterinas , Femenino , Humanos , Miometrio/metabolismo , Leiomioma/genética , Leiomioma/metabolismo , Células Madre/metabolismo , Hormonas/metabolismo , Epigénesis Genética , Neoplasias Uterinas/genéticaRESUMEN
Leiomyomas (LMs) are the most frequent uterine benign tumors, representing the leading cause of hysterectomy indications worldwide. They are highly associated with women's reproductive complications, and endocrine disruptors may influence their etiology. In this sense, air pollution represents a relevant hormonal disruptor that acts on key signaling pathways, resulting in tumor development and infertility. Our goal was to evaluate submucosal LM samples from patients living in the metropolitan and Sao Paulo city regions, focusing on genes involved in tumor development and infertility features. Twenty-four patients were selected based on their region of residence and clinical information availability. Several genes were differentially expressed between women living in metropolitan areas and Sao Paulo city. Significant associations were observed between BCL-2, DVL1, FGFR3, and WNT5b downregulation and contraceptive use in the samples from women living in Sao Paulo city. ESR1 and HHAT downregulation was associated with ethnicity. WNT5b and GREM were associated with LM treatment and related pathologies, respectively. In the samples from women living in other cities of the metropolitan region, abortion occurrence was associated with BMP4 upregulation. Although further studies may be necessary, our results showed that air pollution exposure influences the expression of genes related to LM development and female reproductive features.
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Contaminantes Atmosféricos , Contaminación del Aire , Infertilidad , Leiomioma , Embarazo , Humanos , Femenino , Ciudades , Brasil/epidemiología , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Transcriptoma , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Leiomioma/etiología , Leiomioma/genéticaRESUMEN
Uterine fibroids (UFs) are common tumors in women of reproductive age. It is imperative to comprehend UFs' associated risk factors to facilitate early detection and prevention. Simple relying on surgical/pharmacological treatment of advanced disease is not only highly expensive, but it also deprives patients of good quality of life (QOL). Unfortunately, even if the disease is discovered early, no medical intervention is traditionally initiated until the disease burden becomes high, and only then is surgical intervention performed. Furthermore, after myomectomy, the recurrence rate of UFs is extremely high with the need for additional surgeries and other interventions. This confused approach is invasive and extremely costly with an overall negative impact on women's health. Secondary prevention is the management of early disease to slow down its progression or even halt it completely. The current approach of watchful observation for early disease is considered a major missed opportunity in the literature. The aim of this article is to present an approach named the ESCAPE (Evidence-Based Approach for Secondary Prevention) of UF management. It comprises simple, inexpensive, and safe steps that can arrest the development of UFs, promote overall reproductive health, decrease the number of unnecessary surgeries, and save billions of health care systems' dollars worldwide.