Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Effect of Oral Consumption of Vitamin D on Uterine Fibroids: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Impaired vitamin D status is highly prevalent among women with UFs. The objective of this first-ever systematic review and meta-analysis was to summarize the effect of vitamin D supplementation on the size of uterine fibroids (UFs). We performed a comprehensive literature search for published randomized controlled trials (RCTs) in Medline, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials from inception to September 2022. Five trials including 511 participants (256 cases and 255 controls) were included. Pooling results from five trials, which compared size of UFs between experimental and placebo groups, revealed that vitamin D supplementation could significantly decrease the size of UFs (standardized mean difference [SMD]: -0.48, 95% confidence interval [CI]: -0.66, -0.31) and cause improvement in serum level of vitamin D compared to placebo group (SMD: 3.1, 95% CI: 0.66, 5.55). A significant effect was observed in the subset of trials administering vitamin D supplementation for >8 wk (SMD: -0.62, 95% CI: -0.88, -0.37). In conclusion, vitamin D supplementation significantly increases serum levels of vitamin D and reduces the size of UFs. However, larger, well-designed RCTs are still needed to determine the effect of vitamin D on other parameters of UFs.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

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.

Ameliorative effects of a Chinese herbal formula, fufang meidengmu on uterine leiomyoma in a mice model.

Fufang Meidengmu (FFMDM) is an ethnic herbal medicine form Yunnan province of China, which is often used for the treatment of uterine leiomyoma (UL). Combined Gancao (Glycyrrhiza uralensis Fisch.) and Haizao (Sargassum pallidum (Turn.) C.Ag) in FFMDM represent an herbal pair in the so-called "eighteen antagonistic medicaments" according to traditional Chinese medicine. In this study, we explored the prevention and treatment effects of FFMDM component compatibility on UL in mice. Female Kunming mice were injected for different periods of time with different concentrations of estradiol benzoate (EB) to investigate a feasible method to establish a mice model of UL. Treatment with 0.3mg/kg EB for 15 days was found to be the optimal condition for UL mice models. We then investigate the role of Gancao and Haizao in FFMDM, and explored the underlying mechanism of action of UL mice. Our findings suggested that Gancao and Haizao exerted the favorable effects. In addition, FFMDM is effective in the treatment of UL, and its mechanism was associated with the estrogen (ER) and progesterone receptors (PR).

Contemporary approaches in the management of uterine leiomyomas.

BACKGROUND: Leiomyomas (fibroids), the most common benign solid tumours in females, originate from the myometrium and are associated with poor quality of life for patients. The current management of uterine leiomyomas mainly includes surgical interventions such as hysterectomy and myomectomy, either by laparoscopy or laparotomy, which have several complications and are not ideal for preserving fertility. Therefore, there is a need to develop or repurpose medical treatments that do not require surgical intervention. OBJECTIVE: Many drugs are used to treat the symptoms associated with uterine fibroids. The main objective of this systematic review is to give an up-to-date account of potential pharmacological agents (non-surgical methods) for the management of uterine leiomyomas. SEARCH STRATEGY: PubMed was searched for scientific and clinical literature using the keyword 'uterine fibroids' along with the drug names described in each section. For example, 'uterine fibroids' and 'ulipristal acetate' were the keywords used to search for literature on ulipristal acetate (UPA). RESULTS: Various preclinical and clinical studies have shown that some drugs and herbal formulations exhibit activity in the management of uterine leiomyomas. Recent studies found that drugs such as UPA, elagolix, EC313, asoprisnol, nutritional supplements and herbal preparations were helpful in treating the symptoms associated with uterine leiomyomas. CONCLUSION: Many drugs show efficacy in patients with symptomatic uterine fibroids. UPA is one of the most studied and prescribed medicines for uterine fibroids; however, its usage has been restricted due to a few recent incidences of hepatic toxicity. Herbal drugs and natural supplements have also shown promising effects on uterine fibroids. The synergistic effects of nutritional and herbal supplements have been reported in certain cases, and should be studied in detail. Further research is warranted to identify the mode of action of the drugs, and to determine the precise conditions that would explain the causes of toxicity in some patients.

Curcumol, a major terpenoid from Curcumae Rhizoma, attenuates human uterine leiomyoma cell development via the p38MAPK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Uterine fibroids (UFs) are the most common benign tumors in women of reproductive age. Curcumae Rhizoma, the main essential oil component of which is curcumol, is widely used for the treatment of phymatosis in China due to its antitumor, anti-inflammatory, antithrombin, anti-tissue fibrosis and anti-oxygen pharmacological activities, but its potential for the treatment of UFs has not been evaluated. AIM OF THE STUDY: This study aimed to investigate the effects and mechanisms of curcumol intervention in human uterine leiomyoma cells (UMCs). MATERIALS AND METHODS: Putative targets of curcumol intervention in UFs were identified using network pharmacology strategies. Molecular docking was performed to assess the binding affinity of curcumol to core targets. A concentration gradient of curcumol (0, 50, 100, 200, 300, 400 and 500 µM) or RU-486 (mifepristone, 0, 10, 20, 40, 50, and 100 µM) was applied to UMCs, and cell viability was detected by the CCK-8 assay. Cell apoptosis and cell cycle were examined by flow cytometry, and cell migration was assessed by a wound-healing assay. Additionally, the mRNA and protein expression levels of critical pathway components were evaluated by RT‒PCR and western blotting. Finally, the actions of curcumol on different tumor cell lines were summarized. RESULTS: Network pharmacology predicted 62 genes with roles in the treatment of UFs with curcumol, and MAPK14 (p38MAPK) displayed a higher interaction degree. GO enrichment and KEGG analyses revealed that the core genes were abundantly enriched in the MAPK signaling pathway. The molecular binding of curcumol to core targets was relatively stable. In UMCs, 200, 300 and 400 µM curcumol treatment for 24 h decreased cell viability compared with that in the control group, and the greatest effect was detected at 48 h and maintained until 72 h. Curcumol arrested cells in the G0/G1 phase and subsequently suppressed mitosis, promoted early apoptosis and reduced the degree of wound healing in a concentration-dependent manner in UMCs. Furthermore, 200 µM curcumol decreased the mRNA and protein expression of p38MAPK, the mRNA expression of NF-κB, and the protein expression of Ki-67 and increased the mRNA and protein expression of Caspase 9. Curcumol (300 and 400 µM) decreased the mRNA and protein expression of p38MAPK, NF-κB, and Ki-67 and increased the protein expression of Caspase 9 in UMCs. Curcumol was demonstrated to treat tumor cell lines, including breast cancer, ovarian cancer, lung cancer, gastric cancer, liver cancer and nasopharyngeal carcinoma, but its effects on benign tumors have not yet been reported. CONCLUSION: Curcumol suppresses cell proliferation and cell migration while arresting the cell cycle in the G0/G1 phase and inducing cell apoptosis in UMCs via a mechanism related to p38MAPK/NF-κB pathway regulation. Curcumol may be a potential therapeutic and preventive agent in the treatment of benign tumors such as UFs.

Green Tea and Benign Gynecologic Disorders: A New Trick for An Old Beverage?

Green tea is harvested from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. It is richer in antioxidants than other forms of tea and has a uniquely high content of polyphenolic compounds known as catechins. Epigallocatechin-3-gallate (EGCG), the major green tea catechin, has been studied for its potential therapeutic role in many disease contexts, including pathologies of the female reproductive system. As both a prooxidant and antioxidant, EGCG can modulate many cellular pathways important to disease pathogenesis and thus has clinical benefits. This review provides a synopsis of the current knowledge on the beneficial effects of green tea in benign gynecological disorders. Green tea alleviates symptom severity in uterine fibroids and improves endometriosis through anti-fibrotic, anti-angiogenic, and pro-apoptotic mechanisms. Additionally, it can reduce uterine contractility and improve the generalized hyperalgesia associated with dysmenorrhea and adenomyosis. Although its role in infertility is controversial, EGCG can be used as a symptomatic treatment for menopause, where it decreases weight gain and osteoporosis, as well as for polycystic ovary syndrome (PCOS).

Diagnosis and management of uterine fibroids: current trends and future strategies.

Uterine fibroids (UFs), leiomyomas or myomas, are a type of malignancy that affects the smooth muscle of the uterus, and it is most commonly detected in women of reproductive age. Uterine fibroids are benign monoclonal growths that emerge from uterine smooth muscle cells (myometrium) as well as fibroblasts. Uterine fibroid symptoms include abnormal menstrual bleeding leading to anaemia, tiredness, chronic vaginal discharge, and pain during periods. Other symptoms include protrusion of the abdomen, pain during intercourse, dysfunctions of bladder/bowel leading to urinary incontinence/retention, pain, and constipation. It is also associated with reproductive issues like impaired fertility, conceiving complications, and adverse obstetric outcomes. It is the leading cause of gynaecological hospitalisation in the American subcontinent and a common reason for the hysterectomy. Twenty-five percent of the reproductive women experience the symptoms of uterine fibroids, and among them, around 25% require hospitalization due to the severity of the disease. The frequency of the disease remains underestimated as many women stay asymptomatic and symptoms appear gradually; therefore, the condition remains undiagnosed. The exact frequency of uterine fibroids varies depending on the diagnosis, and the population investigated; nonetheless, the incidence of uterine fibroids in reproductive women ranges from 5.4 percent to 77 percent. The uterine fibroid treatment included painkillers, supplementation with iron, vitamin D3, birth control, hormone therapy, gonadotropin-releasing hormone (GnRH) agonists, drugs modulating the estrogen receptors, and surgical removal of the fibroids. However, more research needed at the level of gene to get a keen insight and treat the disease efficiently.

The efficacy and safety of Chinese herbal medicine Guizhi Fuling capsule combined with low dose mifepristone in the treatment of uterine fibroids: a systematic review and meta-analysis of 28 randomized controlled trials.

OBJECTIVE: Guizhi Fuling Capsule (GZFL), a classic traditional Chinese medicine prescription, is often recommended for the treatment of uterine fibroids (UFs). However, the efficacy and safety of GZFL in combination with low-dose mifepristone (MFP) remains controversial. MATERIALS AND METHODS: We searched eight literature databases and two clinical trial registries for randomized controlled trials (RCTs) of the efficacy and safety of GZFL combined with low-dose MFP in the treatment of UFs from database inception to April 24, 2022. Data analysis was performed using the Meta package in RStudio and RevMan 5.4. GRADE pro3.6.1 software was used for the assessment of evidence quality. RESULTS: Twenty-eight RCTs were included in this study, including a total of 2813 patients. The meta-analysis showed that compared with low-dose MFP alone, GZFL combined with low-dose MFP significantly reduced follicle stimulating hormone (p < 0.001), estradiol (p < 0.001), progesterone (p < 0.001), luteinizing hormone (p < 0.001), uterine fibroids volume (p < 0.001), uterine volume (p < 0.001), menstrual flow (p < 0.001) and increased clinical efficiency rate (p < 0.001). Meanwhile, GZFL combined with low-dose MFP did not significantly increase the incidence of adverse drug reactions compared with low-dose MFP alone (p = 0.16). The quality of the evidence for the outcomes ranged from "very low" to "moderate." CONCLUSION: This study suggests that GZFL combined with low-dose MFP is more effective and safe in the treatment of UFs, and it is a potential treatment for UFs. However, due to the poor quality of the included RCTs formulations, we recommend a rigorous, high-quality, large-sample trial to confirm our findings.

Assessing the Hepatic Safety of Epigallocatechin Gallate (EGCG) in Reproductive-Aged Women.

A similar abstract of the interim analysis was previously published in Fertility and Sterility. EPIGALLOCATECHIN GALLATE (EGCG) FOR TREATMENT OF UNEXPLAINED INFERTILITY ASSOCIATED WITH UTERINE FIBROIDS (PRE-FRIEND TRIAL): EARLY SAFETY ASSESSMENT. Uterine fibroids are the most common cause of unexplained infertility in reproductive-aged women. Epigallocatechin gallate (EGCG), a green tea catechin, has demonstrated its ability to shrink uterine fibroids in prior preclinical and clinical studies. Hence, we developed an NICHD Confirm-funded trial to evaluate the use of EGCG for treating women with fibroids and unexplained infertility (FRIEND trial). Prior to embarking on that trial, we here conducted the pre-FRIEND study (NCT04177693) to evaluate the safety of EGCG in premenopausal women. Specifically, our aim was to assess any adverse effects of EGCG alone or in combination with an ovarian stimulator on serum liver function tests (LFTs) and folate level. In this randomized, open-label prospective cohort, participants were recruited from the FRIEND-collaborative clinical sites: Johns Hopkins University, University of Chicago, University of Illinois at Chicago, and Yale University. Thirty-nine women, ages ≥18 to ≤40 years, with/without uterine fibroids, were enrolled and randomized to one of three treatment arms: 800 mg of EGCG daily alone, 800 mg of EGCG daily with clomiphene citrate 100 mg for 5 days, or 800 mg of EGCG daily with Letrozole 5 mg for 5 days. No subject demonstrated signs of drug induced liver injury and no subject showed serum folate level outside the normal range. Hence, our data suggests that a daily dose of 800 mg of EGCG alone or in combination with clomiphene citrate or letrozole (for 5 days) is well-tolerated and is not associated with liver toxicity or folate deficiency in reproductive-aged women.

Vitamin D and uterine fibroid growth, incidence, and loss: a prospective ultrasound study.

OBJECTIVE: Fibroid treatments that have few side-effects and can preserve fertility are a clinical priority. We studied the association between serum vitamin D and uterine fibroid growth, incidence, and loss. DESIGN: A prospective community cohort study (enrollment 2010-2012) with 4 study visits over 5 years to conduct standardized ultrasounds, measure 25-hydroxyvitamin D (25(OH)D), and update covariates. SETTING: Detroit, Michigan area. PATIENTS: Self-identified African American or Black women aged 23-35 at enrollment without previous clinical diagnosis of fibroids. INTERVENTION(S): Serum 25(OH)D measured using immunoassay or liquid chromatography-tandem mass spectrometry. MAIN OUTCOME MEASURE(S): The primary outcomes were fibroid growth, as measured by change in log volume per 18 months, and fibroid incidence (first detection of fibroid in previously fibroid-free uterus). Adjusted growth estimates from linear mixed models were converted to estimated difference in volume for high vs. low 25(OH)D. Incidence differences were estimated as hazard ratios from age-specific Cox regression. A secondary outcome fibroid loss (reduction in fibroid number between visits), was modeled using Poisson regression. Covariates (reproductive and hormonal variables, demographics, body mass index, current smoking) and 25(OH)D were modeled as time-varying factors. RESULT(S): At enrollment among 1,610 participants with ≥1 follow-up ultrasound, mean age was 29.2 years, 73% had deficient vitamin D (<20ng/mL), and only 7% had sufficient vitamin D (≥30ng/mL). Serum 25(OH)D ≥20ng/mL compared with <20ng/mL was associated with an estimated 9.7% reduction in fibroid growth (95% confidence interval [CI]: -17.3%, -1.3%), similar to the minimally adjusted estimate -8.4% (95% CI: -16.4, 0.3). Serum 25(OH)D ≥30ng/mL compared with <30ng/mL was associated with an imprecise 22% reduction in incidence (adjusted hazard ratio=0.78; 95% CI: 0.47, 1.30), similar to the unadjusted estimate of 0.84 (95% CI: 0.51, 1.39). The >30ng/mL group also had a 32% increase in fibroid loss (adjusted risk ratio=1.32; 95% CI: 0.95, 1.83). CONCLUSION(S): Our data support the hypothesis that high concentrations of vitamin D decrease fibroid development but are limited by the few participants with serum 25(OH)D ≥30ng/mL. Interventional trials that raise and maintain 25(OH)D concentrations >30ng/mL and then prospectively monitor fibroid development are needed to further assess supplemental vitamin D efficacy and determine optimal treatment protocols.

The effect of vitamin D on recurrence of uterine fibroids: A randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: and purpose: A deficiency of vitamin D has been suggested as one of the principal risk factors for uterine fibroids (UFs). We aimed to investigate the effect of vitamin D supplementation on the recurrence of UFs. MATERIALS AND METHODS: In a randomized, double-blind, placebo-controlled pilot study, women who had undergone hysteroscopic myomectomy from November 2017 to June 2020 were randomly given either vitamin D (1000 IU tablet; n = 55), or placebo (n = 54) daily for 12 months. Both groups were followed and compared in regard of the primary outcomes of the study, which were recurrence rates, size, and numbers of UFs based on three-dimensional transvaginal ultrasound investigation (3D-TVS). Data analysis was performed by the intention-to-treat (ITT) approach. RESULTS: The mean age of the study participants was 37.9 ± 6.5 years. The two groups did not differ significantly in terms of demographic and pre-intervention clinical characteristics. The administration of vitamin D supplements for one year reduced recurrence rates of UFs by 50% (p = 0.17). Vitamin D also reduced the size of recurrent UFs in the intervention group compared to controls (-7.7 mm), the difference was statistically different (p < 0.001). No adverse effect of vitamin D was reported in the present study. CONCLUSION: Based on these results, vitamin D appears to be a promising and safe agent in the prevention of recurrence and reduction of the size of recurrent UFs, although further well-designed and appropriately powered studies are required to demonstrate a significant difference in the size and number of recurrent UFs.

Vitamin D and green tea extracts for the treatment of uterine fibroids in late reproductive life: a pilot, prospective, daily-diary based study.

OBJECTIVE: The beneficial effects of Vitamin D (VD) and Epigallocatechin gallate (EGCG), a polyphenol of green tea, on the growth of uterine fibroids (UF) were previously described in vitro and in vivo. We have decided to investigate their simultaneous administration in women with UFs in late reproductive life. METHODS: >40 years old n = 16 premenopausal women with intramural (IM) or subserosal (SS) UF of ≥3 cm or several UFs of different sizes, even smaller but with a total diameter ≥3 cm but <10 cm, without further concomitant organic causes of abnormal uterine bleeding, treated with EGCG 300 mg, Vitamin B6 10 mg and VD 50 µg/day for 90 days. Women completed a diary on a daily basis to obtain information about bleeding and pelvic pain. RESULTS: We have observed a significant reduction in UF's mean size both at patient's (-17.8%, p = .03) and at single UF's level (-37.3%, p = .015). The effect was more evident in women with predominant IM (p = .016) in comparison to SS UFs. No significant changes were observed for uterine and ovarian volume and endometrial thickness during treatment. We reported a significant decrease in menstrual flow length of 0.9 day (p = .04) with no modification in cycle length, menstrual flow intensity and menstrual pain intensity. The satisfaction with treatment was in general very high, with no adverse effects reported. CONCLUSION: The concomitant administration of VD and EGCG represents a promising treatment of UF in women of late reproductive life for which hormonal manipulation is not foreseen.

Randomized double-blind trial comparing low dose and conventional dose of a modified traditional herbal formula Guizhi Fuling Wan in women with symptomatic uterine fibroids.

ETHNOPHARMACOLOGICAL RELEVANCE: The herbal formula Guizhi Fuling Wan is one common remedy for treating uterine fibroids (UFs) and the relevant symptoms in Traditional Chinese Medicine (TCM). Previous systematic reviews showed that Guizhi Fuling Formula appeared to have additional benefit based on mifepristone treatment in reducing volume of fibroids. AIM OF STUDY: To study the efficacy and safety of the conventional dose of a modified herbal formula Guizhi Fuling Wan in patients with symptomatic uterine fibroids in comparison with a sub-effective dose control. MATERIALS AND METHODS: This randomized double-blind, dosage-controlled trial was carried out in an outpatient clinic of traditional Chinese medicine in Hong Kong. Women with symptomatic uterine fibroids diagnosed according to the WHO International Classification of Diseases (ICD-10) were recruited and randomly assigned to one of two groups that received modified Guizhi Fuling Wan at either a low dose or the conventional dose on a daily basis for 16 weeks. This study was quality controlled by a data safety monitoring board. The primary outcome was the symptom severity as measured with the Uterine Fibroid Symptom-Quality of Life questionnaire. The secondary outcomes included quality of life, menstrual bleeding (measured on a pictorial blood loss assessment chart), pain severity (measured on the 6-point behavioral rating scale), change in Chinese medicine syndrome score, fibroid volume (measured by magnetic resonance imaging), hemoglobin level, and hormone levels. RESULTS: Seventy-eight women were recruited for this study. Between-groups comparison showed no significant difference at the endpoint for all outcomes except for the Chinese medicine syndrome score; however, at the endpoint, within-group comparison showed significant improvement in both groups relative to baseline in symptom severity, functional influence of pelvic pain, Chinese medicine syndrome score, and fibroid volume and uterus condition on magnetic resonance imaging (p < 0.05).The low-dose group yielded greater endpoint improvement in the Chinese medicine syndrome score than the conventional-dose group (p=0.024). No serious adverse events related to the intervention were noted. CONCLUSION: Both low-dose and conventional-dose preparations significantly ameliorated uterine fibroid-related symptoms and fibroid volume, although no significant difference was found between the low-dose and conventional-dose groups. The herbal formula GuizhiFuling Wan is safe in women with uterine fibroids.

Nutraceuticals in fibroid management after ulipristal acetate administration: An observational study on patients' compliance.

OBJECTIVE: On May 13, 2020, the Italian government Pharmaceutical Agency (AIFA) stopped ulipristal acetate (UPA) treatments for uterine fibroids (UFs), so patients shifted to other natural treatments. The authors tested the patients' compliance with UF natural treatments. METHODS: Thirty patients of reproductive age (30-45 years) affected by UFs stopped UPA intake and started epigallocatechin gallate (EGCG) plus vitamin D3 treatment. Patients were asked to complete the Uterine Fibroid symptoms and Quality of Life (UFS-QOL) questionnaire, divided into symptoms severity (SS) and health-related quality of life (HRQL), after UPA suspension and to repeat it after 3 months of natural treatment. Collected data were analyzed using paired Student's t test, considering a P value less than 0.05 to be significant. RESULTS: The SS score was significantly lower (-12.19%) for natural treatment when compared with UPA administration. The HRQL score significantly improved (+11.79%) after shifting treatment from UPA to natural therapy. All the investigated parameters appeared improved by 10% after the natural treatment. No adverse effects were reported following the natural treatment. CONCLUSION: Natural treatments showed positive compliance in patients with UFs, based on HRQL score, representing an alternative therapeutic opportunity for patients forced to stop UPA therapy.

Network meta-analysis of 6 kinds of Chinese patent medicines combined with mifepristone in the treatment of uterine fibroids: A protocol for systematic review and network meta-analysis.

BACKGROUND: Uterine fibroids are benign. They belong to the category of "abdominal mass" in traditional Chinese medicine, and pathogenesis is mainly caused by weakness of the body, qi stagnation, and blood stasis. Drug therapy is the preferred treatment of uterine fibroids in clinical practice, and mifepristone is the most commonly used drug. In the past decade, a large number of clinical randomized controlled trials have proven that Chinese patent medicine combined with mifepristone in the treatment of uterine fibroids has a better curative effect, fewer adverse reactions, and higher safety than mifepristone alone. However, there is a lack of evidence-based research. This study aims to integrate clinical data through network meta-analysis to provide more evidence-based medical evidence for clinical medication. METHODS: The comprehensive search included Chinese and other-language databases, such as MEDLINE (PubMed), Web of Science, The Cochrane Library, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China Scientific Journal Database, and China Biomedical Literature Database. Clinical randomized controlled trials of 6 Chinese patent medicines combined with mifepristone for the treatment of uterine fibroids, including Guizhi Fuling Capsule, Gongliuxiao Capsule, Gongliuqing Capsule, Danbie Capsule, Gongliuning Capsule, and Xiaojiean Capsule were retrieved. The search period was from January 2010 to April 2021. Two researchers screened the literature through EndNote and used Excel to extract data. RevMan 5.3 was used to evaluate the quality of the literature. Treatment measures were analyzed in R language, and a forest map and probability ranking map of various interventions were drawn. The network evidence map and correction comparison funnel map of various interventions were drawn by STATA 14.0 software. RESULTS: This study provides the clinical efficacy and safety of network meta-analysis of 6 kinds of Chinese patent medicines combined with mifepristone in the treatment of uterine fibroids will be systematically evaluated or descriptively analyzed. CONCLUSION: This study's purpose is to provide a reference for the clinical treatment of uterine fibroids to choose more effective intervention therapies.

Efficacy of Chinese herbal prescriptions containing Ejiao or Velvet antler for management of uterine fibroids: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate the efficacy and safety of the controversial Chinese herbal prescriptions containing Ejiao or Velvet antler (VA) in the treatment of uterine fibroids. METHODS: We searched 4 famous Chinese databases, the Chinese Clinical Trial Registry, PubMed, Cochrane Central, Google Scholar, Embase, and J-STAGE up to July 2019. We included all eligible randomized controlled trials (RCTs) which compared Chinese herbal prescriptions containing Ejiao or VA (E/VA) with placebo, pharmaceutical intervention, surgery, or other traditional Chinese medicines (TCMs) for uterine fibroids and assessed the risk of bias according to the Cochrane Collaboration's tool. The software Review Manager (RevMan) 5.1 was used for data analysis. RESULTS: A total of 9 RCTs involving 844 patients were identified. Meta-analyses demonstrated that TCM (E/VA) plus mifepristone reduced the volume of uterine fibroids to a greater degree than mifepristone alone [standardized mean difference (SMD): 0.59, 95% CI: 0.33 to 0.85, P<0.00001, I2=50%]; TCM (E/VA) did not enlarge the volume of fibroids when menopausal hormone therapy (MHT) significantly increased the volume (SMD: 1.06, 95% CI: 0.73 to 1.38, P<0.00001, I2=0. The uterine volume change difference was larger via combination therapy of TCM (E/VA) and mifepristone than that of mifepristone (SMD: 0.29, 95% CI: 0.09 to 0.49, P=0.005, I2=0%). The TCM (E/VA) group of had an advantage over the control group in the improvement of fibroid-related symptoms [relative risk (RR): 1.24, 95% CI: 1.15 to 1.35, P<0.00001, I2=0%]. It was found that TCM (E/VA) plus mifepristone could lower estradiol (E2) levels to a greater degree than mifepristone alone (SMD: 1.63, 95% CI: 0.42 to 2.83, P=0.008, I2=97%), as well as progesterone (P) level (SMD: 0.79, 95% CI: 0.55 to 1.04, P<0.00001, I2=43%) in non-menopausal women. A total of 5 studies reported adverse events (AEs), the TCM (E/VA) group was potentially safer than the control group, with lower incidence of AEs (RR: 0.24, 95% CI: 0.15 to 0.40, P<0.00001, I2=25.8%). DISCUSSION: TCM prescriptions containing E/VA seemed superior to the control group in shrinking the volume of uterine fibroids and uterus, improving related symptoms, and reducing non-menopausal women's E2 and P levels, with lower incidence of AEs.

The efficacy and safety of Xuefu Zhuyu Decoction combined with Mifepristone in the treatment of uterine leiomyoma: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Uterine leiomyoma (UL) is a common severe gynecological issue. In China, Xuefu Zhuyu Decoction (XFZYD), combined with Mifepristone, is widely used in the treatment of UL. However, their combined effectiveness and safety for this purpose have not yet been explored. AIM OF THE STUDY: This systematic review aims to evaluate the effectiveness and safety of XFZYD combined with Mifepristone as a method of treatment for UL. MATERIALS AND METHODS: We searched the following 7 databases: 3 English medical databases (PubMed, EMBASE, Cochrane Library), and 4 Chinese medical databases (Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and the Wanfang database). The primary outcome was the effect of XFZYD combined with Mifepristone on the effective rate, uterine leiomyoma volume (ULV), and uterine volume (UV) of uterine leiomyoma. Bias risk was assessed using the Cochrane risk of bias tool. The software RevMan5 was used to evaluate the quality of the included studies and process the data. RESULTS: The 11 studies included in this systematic review were all undertaken in China, with a total of 902 participants. The meta-analysis of XFZYD combined with Mifepristone compared with Mifepristone alone showed that the effective rate (RR 1.20, 95% confidence interval (CI): 1.14-1.27, P < 0.00001), ULV (SMD -1.60, 95% CI: 2.11 to -1.08, P < 0.00001), and UV (SMD -1.65, 95% CI: 1.85 to -1.44, P < 0.00001) in the primary outcomes, and estradiol (E2) (MD -51.81, 95% CI: 69.68 to -33.94, P < 0.00001), luteinizing hormone (LH) (MD -3.09, 95% CI: 3.58 to -2.60, P < 0.00001), follicle stimulating hormone (FSH) (MD -1.09, 95% CI: 1.86 to -0.31, P = 0.006), progesterone (P) (MD -3.55, 95% CI: 4.54 to -2.55, P < 0.00001), and adverse events (RR 0.55, 95% CI: 0.34-0.89), P = 0.01) in the secondary outcomes were significantly reduced, and the data were statistically significant. The subgroups of ULV, E2, and FSH showed that the treatment time might not have been the heterogeneous source of ULV and FSH, but was the heterogeneous source of E2. Sensitivity analysis was carried out on the 3 outcome indicators, and the results were relatively stable after excluding one reference for each indicator. CONCLUSION: There is some encouraging evidence that the combination of XFZYD and Mifepristone can benefit patients by treating UL. However, because of research shortcomings such as lacking allocation concealment and blindness, this study's results should be treated with caution. In order to verify the advantages of this method, it is necessary to carry out further large-scale randomized controlled trials.