Coenzyme Q-10 reduced the aberrant production of extracellular matrix proteins in uterine leiomyomas through transforming growth factor beta 3.

OBJECTIVE: To evaluate the impact of Coenzyme Q-10 (CoQ-10) on the dysregulated synthesis of extracellular matrix proteins mediated by transforming growth factor beta 3 (TGF-ß3) in uterine leiomyomas DESIGN: Laboratory study SUBJECTS: None INTERVENTIONS: Treatment of immortalized uterine myometrial and leiomyoma cells to TGF-ß3 and CoQ-10 MAIN OUTCOME MEASURES: Protein concentration of collagen 1A1 (COL1A1), collagen 3A1 (COL3A1), collagen 11A1 (COL11A1), and fibronectin (FN1) was assessed through western blot analysis after treatment of immortalized uterine myometrial and leiomyoma cells with both TGF-ß3 and concentrations of CoQ-10 at 10, 50, and 100 µM concurrently for 24 hours. RESULTS: Immortalized uterine leiomyoma and myometrial cells exposed to TGF-ß3 for 24 hours demonstrated a significant upregulation of COL1A1, COL3A1, COL11A1, and FN1 as compared to untreated cells. In leiomyoma cells, concurrent treatment with CoQ-10 over the same timeframe revealed a dose-dependent decrease of these protein concentrations as compared to cells treated with TGF-ß3 alone. At the highest concentration of 100 µM CoQ-10, significant decreases in the amount of COL1A1 (0.59 + 0.10-fold, P = 0.03), COL3A1 (0.46 + 0.09-fold, P = 0.002), COL11A1 (0.53 + 0.09-fold, P = 0.01), and FN1 (0.56 + 0.09-fold, P = 0.002) were observed. Similarly, myometrial cells exposed to both TGF-ß3 and CoQ-10 demonstrated a dose-responsive decline in the amount of extracellular matrix protein as compared to cells exposed to TGF-ß3 alone. Significant reductions in the amount of COL1A1 (0.75 + 0.03-fold, P = 0.03), COL3A1 (0.48 + 0.06-fold, P = 0.04), COL11A1 (0.38 + 0.06, P = 0.003), and FN1 (0.69 + 0.04-fold, P = 0.006) were appreciated at 100 µM CoQ-10. CONCLUSION: CoQ-10 mitigated the aberrant production of key biomarkers of the extracellular matrix mediated by TGF-ß3 in uterine leiomyomas. Our findings highlight a promising nonhormonal compound that can counteract the fibroproliferative process inherent to leiomyomas.

Society for Endometriosis and Uterine Disorders Forum: Adenomyosis Today, Paris, France, December 12, 2023.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of Defense, or the United States Government. This symposium was supported by Sumitomo Pharma. However, the authors received no support for the creation of this manuscript, and the manuscript was created, revised and submitted solely by the authors recognized above.

Pathogenesis of uterine fibroids: current understanding and future directions.

Fibroids are benign uterine tumors characterized by the proliferation of uterine smooth muscle cells, embedded in an abundant extracellular matrix. Their prevalence is estimated to be >50% in women aged >45 years. Fibroids represent a considerable health burden. It is time to acquire a deeper mechanistic understanding of uterine fibroid-related etiology and pathogenesis, which may help pinpoint new strategies and an individualized approach. There is a need to gather prospective data and conduct studies to compare alternative approaches and assess long-term outcomes with respect to quality of life, recurrence of symptoms (bleeding and bulk symptoms), fertility, and even complications The goal of this review was to evaluate the widely accepted pathogenesis and identify risks factors and future directions for clinical and basic research into fibroids.

The efficacy of medical management of leiomyoma-associated heavy menstrual bleeding: a mini review.

Leiomyomas, or fibroids, are benign uterine tumors that are commonly associated with abnormal uterine bleeding-L particularly heavy menstrual bleeding (HMB). Treatment options include expectant, medical, image-guided, and surgical. Medical management of HMB is the preferred first-line treatment and includes nonsteroidal anti-inflammatory drugs, contraceptive hormones, tranexamic acid, levonorgestrel intrauterine system, gonadotropin-releasing hormone (GnRH) antagonists and antagonists, selective progesterone receptor modulators, selective estrogen receptor modulators, and aromatase inhibitors. Although alternatives such as vitamins and supplements have been suggested, there is currently a lack of robust evidence of their efficacy. Many of these therapies treat the symptoms rather than the underlying pathology. Progestin-based therapies are the most commonly utilized, although research supporting their effectiveness in the treatment of HMB is modest. Although GnRH agonists and antagonists, which are federal drug administration-approved therapies, provide substantial improvement in abnormal uterine bleeding-L with HMB, the effects typically last for the duration of therapy. Patients may also face financial barriers to GnRH analog therapy. Future studies are required to delineate the nonhormonal treatment options and the long-term management of leiomyoma-associated HMB.

Simvastatin induces degradation of the extracellular matrix in human leiomyomata: novel in vitro, in vivo, and patient level evidence of matrix metalloproteinase involvement.

OBJECTIVES: To assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. DESIGN: Laboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. SETTING: Academic research center. PATIENT(S): Tissue culture from human leiomyoma tissue and surgical leiomyoma tissue sections from a placebo-controlled randomized clinical trial. INTERVENTION(S): Simvastatin treatment. MAIN OUTCOME MEASURE(S): Serum concentrations, xenograft volumes, and protein expression. RESULTS: Mice xenografted with 3-dimensional human leiomyoma cultures were divided as follows: 7 untreated controls; 12 treated with activated simvastatin at 10 mg/kg body weight; and 15 at 20 mg/kg body weight. Simvastatin was detected in the serum of mice injected at the highest dose. Xenograft volumes were significantly smaller (mean 53% smaller at the highest concentration). There was dissolution of compact ECM, decreased ECM formation, and lower collagen protein expression in xenografts. Membrane type 1 matrix metalloproteinase was increased in vitro and in vivo. Matrix metalloproteinase 2 and low-density lipoprotein receptor-related protein 1 were increased in vitro. CONCLUSIONS: Simvastatin exhibited antitumoral activity with ECM degradation and decreased leiomyoma tumor volume in vivo. Activation of the matrix metalloproteinase 2, membrane type 1 matrix metalloproteinase, and low-density lipoprotein receptor-related protein 1 pathway may explain these findings.

The HOPE study: evaluating the impact of an online educational resource for heavy menstrual bleeding on the patient-physician dynamic.

The Heavy menstrual bleeding: Evidence-based Learning for best Practice (HELP) Group developed an educational website about heavy menstrual bleeding (HMB). The "HMB improving Outcomes with Patient counseling and Education" (HOPE) project examined the website's impact on women's knowledge, confidence, and consultations with healthcare providers (HCPs). HOPE was a quantitative online survey of gynecologists and women with HMB in Brazil. After an initial consultation, patients had unlimited access to the website and completed a survey. HCPs also completed a survey about the sconsultation. After a second consultation, HCPs and patients completed another survey. HCP surveys assessed their perception of patients' awareness, understanding, and willingness to discuss HMB. Patient surveys assessed their knowledge, experience, and confidence in discussing HMB. Forty HCPs recruited 400 women with HMB. Based on HCP perceptions at the first consultation, 18 percent of patients had "good knowledge" or "very good knowledge" of HMB, increasing to 69 percent after patients had visited the website. Before and after visiting the website, 34 percent and 69 percent of patients, respectively, regarded their HMB knowledge as "goo.d" Additionally, 17 percent of women reported their anxiety as "highest" during the first consultation; this decreased to 7 percent during the second consultation. After visiting the HELP website, patients' knowledge of HMB improved and they were less anxious.

Curcumin inhibits human leiomyoma xenograft tumor growth and induces dissolution of the extracellular matrix.

OBJECTIVE: To determine whether a curcumin-supplemented diet would prevent and/or treat uterine leiomyoma growth in our mouse xenograft model. DESIGN: Animal study. SETTING: Laboratory study. PATIENT(S): N/A. INTERVENTION(S): Curcumin-supplemented diet. MAIN OUTCOME MEASURE(S): Dietary intake, blood concentrations, tumor size, extracellular matrix protein concentrations, apoptosis markers. RESULT(S): We found that curcumin was well tolerated as a dietary supplement, free curcumin and its metabolites were detected in the serum, and exposure resulted in approximately 60% less leiomyoma xenograft growth as well as dissolution of the peripheral extracellular matrix architecture of the xenografts. The production of matrix proteins, including collagens, decreased, whereas the number of apoptotic cells in the xenografts increased. Additionally, when xenografts were placed in a uterine intramural location, we found a significantly increased apoptotic response to curcumin in the diet. CONCLUSION(S): Mice on a diet supplemented with curcumin could achieve serum concentrations sufficient to regulate human leiomyoma xenograft growth, and curcumin could play both preventive and curative roles in the treatment of uterine leiomyoma as an oral nutritional supplement.

Relugolix and elagolix directly inhibit leiomyoma extracellular matrix production in 2-dimesnional and 3-dimensional cell cultures.

OBJECTIVE: To determine the effect relugolix and elagolix have on the production of extracellular matrix (ECM) proteins in human leiomyoma cells. DESIGN: Laboratory study. SETTING: University hospital. PATIENT(S) OR ANIMALS: None. January 5, 2022 Cell culture, protein analysis, immunohistochemistry. MAIN OUTCOME MEASURE(S): Production of GnRHR, COL1A1, FN1, VCAN, p-ERK, & ERK in treated/untreated leiomyoma cells. RESULTS: 100 nM relugolix resulted in decreased production of COL1A1 at 24 (1.78 0.06-fold; P < .05) and 48 hours (1.92 0.14-fold; P < .05). Elagolix treatment resulted in a decrease in COL1A1 production at 24 but not 48 hours. In 2D and 3D, 100 nM relugolix resulted in decreased production of FN1 at 24 (1.7 ± 0.07-fold; P < .05) and 48 hours (1.8 ± 0.07-fold; P < .05); 100 nM elagolix resulted in decreased production of FN1 at 24 (1.7 ± 0.14-fold; P < .05) and 48 hours (2.0 ± 0.09-fold; P < .05). For cells treated with relugolix 100 nM resulted in decreased VCAN production by 48 hours (0.66 ± 0.07-fold; P < .05). Contrary to our 3D data, 2D elagolix-treated cells demonstrated a decrease in VCAN production that was identified only at 24 hours. For GnRHR, no significant difference between the drugs was seen at 24 hours; at 48 hours production was only significantly decreased for relugolix (P < .05). Comparing both drugs, there was a significant difference in the concentration of p-ERK to ERK at 24 hours (P < .05); there was no difference by 48 hours. CONCLUSIONS: Our findings demonstrated that treatment with either drug can 1) decrease ECM protein production and 2) inhibit the MAPK pathway.

A Review of GnRH Antagonists as Treatment for Abnormal Uterine Bleeding-Leiomyoma (AUB-L) and Their Influence on the Readiness of Service Members.

INTRODUCTION: Not too long ago, Lupron Depot® (leuprolide acetate), an injectable gonadotropin-releasing hormone (GnRH) agonist, was the only Food and Drug Administration (FDA) approved GnRH analog used to clinically treat abnormal uterine bleeding associated with uterine leiomyoma (AUB-L) when second-line medical management was warranted; however, the FDA has now approved elagolix and relugolix, GnRH antagonists, to be treatment options as well. This is a review of GnRH antagonists for the management of uterine fibroids reviewing their treatment efficacy, side effect profile, and current use in military medicine. METHODS: This is a review of studies from multiple electronic databases (Pubmed, ACOG, FDA, U.S. Military Guidelines) published between 1990 and 2021. Keywords used for the search include GnRH antagonist, elagolix, relugolix, uterine leiomyoma, and abnormal uterine bleeding. Our inclusion criteria for articles reviewed were: systematic reviews with the listed keywords, multicenter randomized trials, and meta-analyses. The DODI on Medical Standards for Medical Service, Air Force Aerospace Medicine Waiver Guide, Navy Guidance Aeromedical Reference and Waiver Guide, and the Army Regulation 40-501 Standards of Medical Fitness were used to review the military standards and current restrictions placed on service members. RESULTS: Thirty-three articles were reviewed and summarized. CONCLUSION: Uterine leiomyoma can impact service members' eligibility and fitness for duty. The oral administration of elagolix and relugolix adds convenience to this drug class through its oral administration while lengthening the duration of treatment up to 24 months. All military medical facilities should advocate for the well-being of their service members by stocking all options available. Health care providers should collaborate with patients in making the best therapy choice that is suited for their lifestyle and military occupation.