[Is there still a place for progesterone receptor modulators in chronic use ?] / Cas clinique. Y a-t-il encore une place pour les modulateurs du récepteur de la progestérone en continu ?

Selective progesterone receptor modulators (SPRMs) are synthetic steroid compounds that interact with the progesterone receptor, inducing various agonist, antagonist or mixed responses. First identified with mifepristone, they are now represented by ulipristal acetate (UPA), used for emergency contraception and uterine fibroids. Despite a few rare cases of severe hepatic insufficiency, SPRMs offer advantages in the treatment of uterine fibroids, reducing their volume without the hypoestrogenic side-effects of GnRH agonists, thus preserving patients' bone capital and quality of life. Despite temporary suspension of UPA administrated on a daily basis, research is exploring the potential of SPRMs in the management of endometriosis, adenomyosis and breast cancer. Despite certain concerns, SPRMs offer promising prospects in gynecological pathologies, opening up new therapeutic avenues to improve women's health and quality of life. This article describes the case of a patient with peritoneal leiomyomatosis for whom UPA significantly alleviated symptoms, reduced disease progression and improved quality of life, even allowing a pregnancy.

Les modulateurs sélectifs des récepteurs de la progestérone (SPRMs) sont des composés stéroïdiens synthétiques qui interagissent via le récepteur de la progestérone, induisant diverses réponses, agonistes, antagonistes ou mixtes. Les SPRMs ont d'abord été représentés par la mifépristone, utilisée pour ses propriétés antagonistes dans la gestion de l'interruption de la grossesse, puis par l'acétate d'ulipristal, qui est indiqué en contraception d'urgence, mais aussi pour la gestion de myomes utérins symptomatiques. Les SPRMs permettent de réduire le volume des myomes utérins, sans induire les effets secondaires d'hypo-œstrogénie des agonistes de la GnRH, préservant ainsi le capital osseux et la qualité de vie des patientes. Néanmoins, quelques cas graves d'insuffisance hépatique ont conduit à la suspension temporaire de l'acétate d'ulipristal en traitement chronique. En dépit de certaines réserves, les SPRMs offrent des perspectives dans les affections gynécologiques, ouvrant de nouvelles voies thérapeutiques pour améliorer la santé et la qualité de vie des femmes. Des recherches explorent leur potentiel dans l'endométriose, l'adénomyose et la chimioprévention du cancer du sein. Nous décrivons ici le cas d'une patiente avec léiomyomatose péritonéale pour laquelle l'acétate d'ulipristal a significativement réduit les symptômes et l'évolution de la maladie, tout en améliorant la qualité de vie de la patiente, avec même l'obtention d'une grossesse menée à terme.

Dispensing patterns of antidepressant and antianxiety medications for psychiatric disorders after benign hysterectomy in reproductive-age women: Results from group-based trajectory modeling.

BACKGROUND: Women with gynecologic disorders requiring a hysterectomy often have co-existing psychiatric diagnoses. A change in the dispensing pattern of antidepressant (AD) and antianxiety (AA) medications around the time of hysterectomy may be due to improvement in gynecologic symptoms, such as pelvic pain and abnormal bleeding, or the emotional impact of the hysterectomy. Unfortunately, these dispensing patterns before and after hysterectomy are currently undescribed. OBJECTIVES: To model the dispensing patterns of AD and AA medications over time among women with psychiatric disorders before and after benign hysterectomy for endometriosis and uterine fibroids; and to characterize clusters of patients with various dispensing behaviors based on these patterns. DESIGN: Retrospective cohort study. METHODS: This is a study of women who underwent a benign hysterectomy using data from the Merative MarkertScan® Research Databases (Ann Arbor, MI, USA). Inclusion criteria were reproductive-aged women (18-50 years), diagnosis of at least one mood or anxiety disorder, and at least one dispensing of AD or AA medications. We measured monthly adherence and persistence of AD/AA medication use over 12 months after hysterectomy. Group-based-trajectory modeling (GBTM) was used to identify trajectory groups of monthly AD/AA medication dispensing over the study period. Multinomial logistic regression was used to identify factors independently associated with individual dispensing trajectory patterns. RESULTS: For a total of 11,607 patients, 6 dispensing trajectory groups were identified during the study period: continuously high (27.0%), continuously moderate (21.9%), continuously low (17.9%), low-to-high (10.0%), moderate-to-low (9.8%), and low-to-moderate (13.4%). Compared with the continuously high group, younger age, no history of a mood disorder, and uterine fibroids were clinical predictors of low dispensing. The discontinuation rate at 3 months after hysterectomy was higher at 88.6% in the continuously low group and at 66.5% in the continuously low-to-moderate group. CONCLUSIONS: This study demonstrates that GBTM identified six distinct trajectories of AD/AA medication dispensing in the perioperative period. Trajectory models could be used to identify specific dispensing patterns for targeting interventions.

Dispensing patterns of antidepressant and antianxiety medications for psychiatric disorders after benign hysterectomy in reproductive-aged women: Results from the group-based trajectory modelingWomen with gynecologic disorders often have coexisting psychiatric diagnoses. A change in the dispensing pattern of antidepressant and antianxiety medications may be due to improvement in gynecologic symptoms or the emotional impact of the hysterectomy. However, static measures, such as the proportion of days covered or medication possession ratio, may not adequately predict meaningful dispensing patterns. Using the group-based trajectory modeling, 6 distinct patterns of medication dispensing over the perioperative periods of women with benign hysterectomy are identified and therefore used to assess how certain clinical characteristics influence these dispensing patterns. This study concludes that trajectory modeling may be a more appropriate approach to investigating dispensing patterns among women with preexisting psychiatric conditions.

Uterine fibroids: current research on novel drug targets and innovative therapeutic strategies.

INTRODUCTION: Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy. AREAS COVERED: This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy. EXPERT OPINION: While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

In Vivo Effects of Bay 11-7082 on Fibroid Growth and Gene Expression: A Preclinical Study.

Current medical therapies for fibroids have major limitations due to their hypoestrogenic side effects. Based on our previous work showing the activation of NF-kB in fibroids, we hypothesized that inhibiting NF-kB in vivo would result in the shrinkage of tumors and reduced inflammation. Fibroid xenografts were implanted in SCID mice and treated daily with Bay 11-7082 (Bay) or vehicle for two months. Bay treatment led to a 50% reduction in tumor weight. RNAseq revealed decreased expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) composition, and growth factor expression. Validation through qRT-PCR, Western blotting, ELISA, and immunohistochemistry (IHC) confirmed these findings. Bay treatment reduced mRNA expression of cell cycle regulators (CCND1, E2F1, and CKS2), inflammatory markers (SPARC, TDO2, MYD88, TLR3, TLR6, IL6, TNFα, TNFRSF11A, and IL1ß), ECM remodelers (COL3A1, FN1, LOX, and TGFß3), growth factors (PRL, PDGFA, and VEGFC), progesterone receptor, and miR-29c and miR-200c. Collagen levels were reduced in Bay-treated xenografts. Western blotting and IHC showed decreased protein abundance in certain ECM components and inflammatory markers, but not cleaved caspase three. Ki67, CCND1, and E2F1 expression decreased with Bay treatment. This preclinical study suggests NF-kB inhibition as an effective fibroid treatment, suppressing genes involved in proliferation, inflammation, and ECM remodeling.

Life-threatening vaginal bleeding after starting rivaroxaban treatment.

This is a case report of a 44-year-old premenopausal woman who was admitted to hospital due to uncontrollable and life-threatening vaginal bleeding after starting rivaroxaban treatment for atrial fibrillation. She had a medical history with menorrhagia due to an intrauterine fibroma. She did not respond sufficiently to factor X supplement or other non-surgical medical interventions. The bleeding subsided after bilateral embolization of aa. uterinae.

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

WHAT IS THIS SUMMARY ABOUT?: This is a summary of findings from two research studies (known as clinical trials). The studies looked at how well a medicine called relugolix combination therapy worked in women with heavy menstrual bleeding (heavy bleeding during a period) with uterine fibroids (noncancerous or benign growths in the uterus). In this analysis of the studies, researchers looked at how patients self-reported their uterine fibroid symptoms before and after taking relugolix combination therapy. Researchers also looked at how patients self-reported the impact of uterine fibroids on their health-related quality of life before and after taking relugolix combination therapy. WHAT WERE THE RESULTS?: Women took either relugolix combination therapy or placebo (a pill that contains no medicine) by mouth once daily for 24 weeks. Women completed the Uterine Fibroid Symptom and Quality of Life questionnaire (where "quality of life" refers to the women's health-related quality of life related to uterine fibroids) before, during, and after treatment. The questionnaire let researchers see if the women felt that relugolix combination therapy decreased the burden of uterine fibroid symptoms and improved the women's health-related quality of life related to uterine fibroids. More women said that they felt less distress due to their uterine fibroid symptoms and that their health-related quality of life related to uterine fibroids was better after taking relugolix combination therapy compared with women who took placebo. WHAT DO THE RESULTS MEAN?: Relugolix combination therapy may lessen distress associated with uterine fibroid symptoms and improve health-related quality of life related to uterine fibroids.

Advancements and Emerging Therapies in the Medical Management of Uterine Fibroids: A Comprehensive Scoping Review.

Uterine fibroids, benign tumors originating from uterine smooth muscle cells, vary in prevalence depending on patient ethnicity, hormonal exposure, and genetics. Due to their high incidence, these neoplasms pose a significant burden on healthcare systems. Current treatment strategies range from routine monitoring in asymptomatic cases to surgical procedures such as myomectomy or hysterectomy in symptomatic patients, with an increasing trend toward uterus-preserving or non-surgical alternatives. This review examines the existing medical treatments for uterine fibroids and delves into the potential of emerging therapies. A scoping review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Medical therapies are divided into hormonal and non-hormonal treatments; however, long-term, safe, and effective treatments in the treatment of uterine fibroids are limited. In addition to established therapies, there is an increasing number of studies investigating the effect of substances such as vitamin D or green tea extract on uterine fibroids. Some studies investigate acupuncture as a possible alternative therapy. While existing treatments offer symptomatic relief and preparation for surgery, our findings point to a significant need for further research into long-term solutions, especially owing to recent limitations in the use of ulipristal acetate due to risk of liver damage. Initial studies involving vitamin D and epigallocatechin gallate are encouraging; however, additional research is required to establish definitive therapeutic roles.

The effectiveness of relugolix compared with leuprorelin for preoperative therapy before laparoscopic myomectomy in premenopausal women, diagnosed with uterine fibroids: protocol for a randomized controlled study (MyLacR study).

BACKGROUND: The oral gonadotropin-releasing hormone antagonist relugolix, which temporarily stops menstruation, is used to treat heavy menstrual bleeding, pelvic pressure, and low back pain in women with uterine fibroids. Treatment can also help women recover from low hemoglobin levels and possibly shrink the fibroids. However, evidence of preoperative use of relugolix before laparoscopic myomectomy is limited. Nevertheless, the treatment could reduce interoperative blood loss, decrease the risk of developing postoperative anemia, and shorten the operative time. Thus, we aim to test whether 12-week preoperative treatment with relugolix (40 mg orally, once daily) is similar to or not worse than leuprorelin (one injection every 4 weeks) to reduce intraoperative blood loss. METHODS: Efficacy and safety of preoperative administration of drugs will be studied in a multi-center, randomized, open-label, parallel-group, noninferiority trial enrolling premenopausal women ≥ 20 years of age, diagnosed with uterine fibroids and scheduled for laparoscopic myomectomy. Participants (n = 80) will be recruited in the clinical setting of participating institutions. The minimization method (predefined factors: presence or absence of fibroids ≥ 9 cm and the International Federation of Gynecology and Obstetrics [FIGO] type 1-5 fibroids) with randomization is used in a 1:1 allocation. Relugolix is a 40-mg oral tablet taken once a day before a meal, for 12 weeks, up to the day before surgery. Leuprorelin is a 1.88 mg, or 3.75 mg subcutaneous injection, given in three 4-week intervals during patient visits before the surgery. For the primary outcome measure of intraoperative bleeding, the blood flow is collected from the body cavity, surgical sponges, and collection bag and measured in milliliters. Secondary outcome measures are hemoglobin levels, myoma size, other surgical outcomes, and quality-of-life questionnaire responses (Kupperman Konenki Shogai Index and Uterine Fibroid Symptoms-Quality of Life). DISCUSSION: Real-world evidence will be collected in a clinical setting to use pre-treatment with an oral gonadotropin-releasing hormone antagonist to reduce intraoperative bleeding in women who undergo laparoscopic myomectomy. TRIAL REGISTRATION: jRCTs031210564 was registered on 19 January 2022 in the Japan Registry of Clinical Trials ( https://jrct.niph.go.jp ).

The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

Experimental and new investigational drugs for the treatment of uterine fibroids.

INTRODUCTION: Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations. AREAS COVERED: This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids. EXPERT OPINION: Despite ulipristal acetate's well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

Quality of life improvements in women with uterine fibroids treated with relugolix combination therapy during the LIBERTY long-term extension study: A descriptive subgroup analysis in women with anemia at baseline.

OBJECTIVE: To investigate the effects of 52 weeks of treatment with relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) on symptoms of uterine fibroids (UF) and quality of life (QoL) in women with heavy menstrual bleeding associated with UF and anemia (hemoglobin ≤10.5 g/dL) at baseline. METHODS: This post hoc analysis included women from the LIBERTY long-term extension study with anemia (hemoglobin concentration ≤10.5 g/dL) at pivotal study baseline and documented hemoglobin values at week 52 (anemia-evaluable population). Treatment responders: women achieving a menstrual blood loss volume of <80 mL and a ≥50% reduction over the last 35 days of treatment. Anemia responders were women achieving a hemoglobin increase of >2 g/dL from baseline to week 52. Least squares (LS) mean changes from baseline in uterine fibroid symptom (UFS)-QoL symptom severity, fatigue, and health-related QoL total (HR-QoL) and (sub)scale scores were calculated. RESULTS: In total, 115 women were included in the anemia-evaluable population. Of 39 anemia-evaluable women who received continuous treatment with relugolix combination therapy for 52 weeks, 34 (87.2%) met treatment responder criteria and 23 (59.0%) were anemia responders. LS mean hemoglobin concentration increased by 29.4% at week 52. LS mean UFS-QoL symptom severity and fatigue scores decreased by 38.5 and 31.9 points, respectively, and HR-QoL total score increased by 41.6 points. CONCLUSION: In women with UF and a high disease burden due to anemia, relugolix combination therapy substantially improved hemoglobin levels, decreased distress due to symptoms, especially fatigue, over 52 weeks.

Functional evidence for two distinct mechanisms of action of progesterone and selective progesterone receptor modulator on uterine leiomyomas.

OBJECTIVE: To study the specific mechanisms through which progesterone and selective progesterone receptor modulators impact the growth, synthesis, and accumulation of the extracellular matrix in uterine leiomyomas. DESIGN: Laboratory study. SETTING: Academic Research Institutions. PATIENTS (S): This study involved reproductive-age women diagnosed with infertility associated uterine leiomyomas who underwent myomectomy either after selective progesterone receptor modulator ulipristal acetate (UA) treatment or without any pharmacological pretreatment. Control samples included healthy myometrium tissue (n = 100). Specimens were obtained from the Department of Reproduction and Gynecological Endocrinology and Biobank, Medical University of Bialystok, Poland. INTERVENTIONS: Daily (5 mg/d) UA treated for 2 months (n = 100) and untreated (n = 150) patients with uterine leiomyomas or normal healthy myometrium (n = 100) tissue samples immediately after surgery were collected for transcriptional analysis and assessments. MAIN OUTCOME MEASURES: Progesterone-induced activation of the signaling pathways related to uterine leiomyomas extracellular matrix synthesis, deposition, and growth, as well as the expression profile of progesterone receptors in uterine leiomyomas, were assessed. RESULTS: The results indicated that progesterone activated the transforming growth factor-ß and SMAD3 signaling pathways and promoted proliferation, growth, and extracellular matrix remodeling in uterine leiomyomas by up-regulating SMAD3, transforming growth factor-ß (TGF-ß) receptor type 1 and II, Ras homolog A, vascular endothelial growth factor, or increasing the fibrosis-related gene collagen, type I, ɑ-1, and procollagen, type I, ɑ-1 production. In contrast, UA had inhibitory effects on these processes. The study also showed that both nuclear and membrane progesterone receptors play distinct roles in uterine leiomyoma pathobiology. CONCLUSIONS: We showed that both nuclear and membrane progesterone receptors were relevant in the treatment of uterine leiomyomas, especially when combined with selective progesterone receptor modulators. Novel therapeutic approaches combining selective progesterone receptor modulators with or without direct and indirect extracellular matrix targeting through selected specifically TGF-ß and SMAD3 (SMAD3, TGF-ß receptor types 1 and II, Ras homolog A, vascular endothelial growth factor, collagen, type I, ɑ-1) signaling pathways could therefore be a treatment option for uterine leiomyomas.

Network-based drug repositioning of linagliptin as a potential agent for uterine fibroids targeting transforming growth factor-beta mediated fibrosis.

Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-ß (TGF-ß), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids.

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.

The clinical trial of alternative relugolix administration for uterine leiomyoma prior to surgically treatment: a study protocol for Non-Adverse Relugolix Administration (NARA) trial.

BACKGROUND: Uterine leiomyomas are common for reproductive-aged women and affect women's quality of life due to heavy menstrual bleeding or dysmenorrhea. Leiomyomas grow according to estradiol exposure and decrease after post-menopause. In case serious symptoms are caused by leiomyomas, pharmacotherapy or surgical treatment is proposed. Prior to surgical treatment, pharmacotherapies aimed at the reduction of leiomyoma and uterine volume or improvement of anemia are introduced to conduct minimum invasive surgery (i.e., to reduce blood loss or surgical duration). Recently, relugolix (40 mg orally once daily) as a gonadotropin-releasing hormone (GnRH) receptor antagonist has proved its sufficient efficacy in suppressing estradiol levels without the transient estradiol flare-up compared with GnRH agonist. However, long-term administration should not be permitted liable to for climacteric disorder or osteoporosis, and evidence is lacking on the actual efficacy and extent of adverse effects of the every-other-day dosing regimen. This trial aimed to prove non-inferiority in volume reduction effect on leiomyoma and safety (i.e., reduction of adverse effects) by every-other-day administration after 2 months of everyday administration compared to daily administration throughout the duration. METHODS: A minimization adaptive randomized control trial (RCT) will be conducted. Patients (over 20 years old) harboring leiomyoma who will be undergoing surgical treatment will be invited to participate. Patients who are enrolled in the intervention group will receive every-other-day administration for 16 weeks after 8 weeks of daily administration. Patients who are enrolled in the control group will receive daily throughout the 24 weeks. The primary outcome is the leiomyoma volume reduction, and the secondary endpoints are the reduction of uterine volume, the occurrence of the climacteric disorder, genital bleeding days, change rate of serum hormone or bone turnover markers, and bone mineral density after 24 weeks compared to before administration. DISCUSSION: This study aims to prove both the non-inferiority in leiomyoma volume reduction and superiority in adverse effects occurrence reduction, which will provide a novel method to escape adverse effects while maintaining the effect of leiomyoma reduction. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023.

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.

The impact of epigallocatechin gallate, vitamin D, and D-chiro-inositol on early surgical outcomes of laparoscopic myomectomy: a pilot study.

PURPOSE: A prospective investigation to assess the impact of 3 months of treatment with epigallocatechin gallate (EGCG), vitamin D and D-chiro-inositol (DCI) in the treatment of uterine fibroids (UF) with laparoscopic myomectomy as evidenced by surgical outcomes and effect on liver function. METHODS: Non-pregnant or lactating women aged between 30 and 40 years were scheduled for laparoscopic myomectomy to treat symptoms or looking to conceive. After enrollment, patients were assigned to either (1) intervention group, assuming a total of 300 mg EGCG, 50 µg vitamin D, and 50 mg DCI divided in 2 pills per day for 3 months, or (2) control group, including untreated women scheduled to undergo laparoscopic myomectomy after 3 months. RESULTS: 91 patients completed the study. The comparison of the surgical outcomes between the intervention (n = 44) and the control (n = 47) groups revealed that the treatment significantly reduces the duration of surgery (41.93 ± 7.56 min vs 56.32 ± 10.63 min, p < 0.001). Moreover, the treatment also reduced blood loss during surgery (149.09 ± 25.40 mL vs 168.41 ± 21.34 mL, p < 0.001), resulting in treated patients having higher Hb levels at discharge 11.27 ± 0.82 mL vs 10.56 ± 0.82 mL, p < 0.01). The surgery induced an increase in AST and in total bilirubin regardless of the assigned group, and the treatment induced no change in liver function. CONCLUSIONS: Our data suggest that EGCG plus vitamin D, and DCI could represent a safe option for women with UF scheduled for laparoscopic myomectomy, improving surgical outcomes without affecting liver functionality.

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.