Empowering Strategies for Lifestyle Interventions, Diet Modifications, and Environmental Practices for Uterine Fibroid Prevention; Unveiling the LIFE UP Awareness.

Uterine fibroids (UFs) are the most common prevalent benign tumor among women of reproductive age, disproportionately affecting women of color. This paper introduces an innovative management strategy for UFs, emphasizing the curbing of disease prevention and progression. Traditionally, medical intervention is deferred until advanced stages, necessitating invasive surgeries such as hysterectomy or myomectomy, leading to high recurrence rates and increased healthcare costs. The strategy, outlined in this review, emphasizes UF disease management and is named LIFE UP awareness-standing for Lifestyle Interventions, Food Modifications, and Environmental Practices for UF Prevention. These cost-effective, safe, and accessible measures hold the potential to prevent UFs, improve overall reproductive health, reduce the need for invasive procedures, and generate substantial cost savings for both individuals and healthcare systems. This review underscores the importance of a proactive UF management method, paving the way for future research and policy initiatives in this domain.

Evidence-Based Approach for Secondary Prevention of Uterine Fibroids (The ESCAPE Approach).

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.

A Systematic Review of Vitamin D and Fibroids: Pathophysiology, Prevention, and Treatment.

Uterine fibroids are the most common tumor of reproductive-age women worldwide and cause significant morbidity in affected women. Vitamin D has emerged as a potential therapy for uterine fibroids based on experimental and epidemiologic evidence. The objective of this systematic review was to evaluate the role of vitamin D in the pathophysiology of uterine fibroids and its efficacy for prevention and treatment of fibroids. A comprehensive search was conducted of Cochrane Library, Embase, PubMed, Scopus, and Web of Science from inception to March 2022. English-language publications that evaluated vitamin D and uterine fibroids in humans, whether experimental or clinical, were considered. The search yielded 960 publications, and 89 publications met inclusion criteria: 23 preclinical studies, 25 clinical studies, and 41 review articles. Preclinical studies indicated that the vitamin D receptor was decreased in fibroid cells. Vitamin D treatment of fibroid cells decreased proliferation, extracellular matrix protein expression, and Wnt/ß-catenin signaling. Fourteen clinical studies (n = 3535 participants) assessed serum vitamin D level in women with ultrasound-proven fibroids, and all found an inverse correlation between serum vitamin D level and presence of fibroids. Five clinical studies (n = 472 patients) evaluated treatment of fibroids with vitamin D. Four of five studies showed vitamin D significantly inhibited fibroid growth. One pilot study (n = 109 patients) of vitamin D for secondary prevention of fibroids demonstrated smaller recurrent fibroids in the treated group. These studies provide evidence for vitamin D as a therapy for uterine fibroids and underscore the need for well-designed, randomized, placebo-controlled clinical trials.

The Future of Uterine Fibroid Management: a More Preventive and Personalized Paradigm.

Uterine fibroids are the most common tumors of the female reproductive tract, affecting up to 80% of women. Despite their heavy burden and high prevalence, available medical treatment options are limited and are offered to patients assuming equal responsiveness. These benign tumors are complex, originating from potentially diverse pathobiologic processes, yet they are all managed in a rather standardized symptom-oriented approach that does not take into account the underlying processes. With our increasing understanding of the interplay between genes, epigenetics, individual's lifestyle, and the environment in disease development, uterine fibroid management should be geared towards individualized preventive and treatment options. For example, it seems that some subsets of patients with fibroids also suffer from vitamin D deficiency, hypertension, metabolic syndrome, or other conditions. It is possible that these subsets may have different underlying processes and different responsiveness to different treatment options. Herein, we call for a futuristic paradigm shift of research to develop a new model to manage uterine fibroids with the treatment approach varying depending on the patient's perceived underlying processes as assessed by medical, social, family history, and relevant investigations. This is only possible through the collaboration of scientists, physicians, and funding agencies and with the help of our patients.

Vitamins and Uterine Fibroids: Current Data on Pathophysiology and Possible Clinical Relevance.

Uterine fibroid (UF) is the most common benign tumor pathology of the female reproductive organs. UFs constitute the main reason for a hysterectomy and hospitalization due to gynecological conditions. UFs consist of uterine smooth muscle immersed in a large amount of extracellular matrix (ECM). Genetic studies have demonstrated that UFs are monoclonal tumors originating from the myometrial stem cells that have underwent specific molecular changes to tumor initiating stem cells which proliferate and differentiate later under the influence of steroid hormones. There is growing interest in the role of micronutrients, for example, vitamins, in UFs. This article is a comprehensive review of publications regarding the available data concerning the role of vitamins in the biology and management of UFs. In summary, the results showed that some vitamins are important in the biology and pathophysiology of UFs. For example, vitamins A and D deserve particular attention following studies of their influence on the treatment of UF tumors. Vitamins B3, C, and E have not been as widely studied as the abovementioned vitamins. However, more research could reveal their potential role in UF biology.

Prescription of Chinese herbal products is associated with a decreased risk of uterine fibroids: A population-based cohort study.

The finding of a decrease in subsequent fibroid-related operation following the use of Chinese herbal products (CHPs) has led to speculation that CHPs might play a role in uterine fibroids prevention.This study provides an overview of uterine fibroids incidence, comparing CHP users with those who do not use CHPs, referred to as non-CHP users. The results can provide information to clinicians for counseling women about the preventive use of CHPs.A total of 52,151 women (20-45 years of age) were recruited from a nationwide 1-million-person representative sample of those covered by National Health Insurance in Taiwan and were followed from 2000 to 2013. Exact matching was performed for comparative analysis. The age-specific hazard ratios (HRs) of uterine fibroids in relation to either CHP or the phytoestrogen use were calculated with multivariate Cox proportional hazard regression.More than 71% of patients had used a CHP at some point previously. The overall incidence density rate of uterine fibroids for non-CHP users was estimated at 27.5 per 1000 patient-years. The corresponding values for CHP and the phytoestrogen users were lower than those of the non-CHP group (CHP group = 15.5; the phytoestrogen group = 12.5 per 1000 patient-years). The covariate adjusted HRs for uterine fibroid were 0.73 (95% confidence interval [CI] 0.63-0.85) and 0.65 (95% CI 0.52-0.82) in women using CHPs and the phytoestrogen, respectively.CHPs seem to contribute to a decreased risk in developing uterine fibroids. Although the mechanism of action of these products is unclear, their use as a preventive agent for uterine fibroids might be taken into consideration.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extract and Active Compounds Inhibit Proliferation of Primary Human Leiomyoma Cells and Protect against Sexual Hormone-Induced Mice Smooth Muscle Hyperproliferation.

Uterine leiomyomas, also known as fibroids, are benign neoplasms of the uterus and have a high incidence rate in women of reproductive age. Hysterectomy or myomectomy is the initial treatment, but fibroids will recur if the patient is still exposed to similar risk factors. Therefore, developing new therapeutic strategies are urgently necessary. In this study, the anti-proliferation effects of each fraction of adlay seeds were evaluated in uterine leiomyomas, and we identified the potential phytochemical compounds. We found that the ethyl acetate fraction of adlay hull (AHE-ea) appeared to be highly efficient in the anti-proliferation of rat uterine leiomyoma ELT3 cells and primary human uterine leiomyoma (hUL) cells. The proliferation of primary human normal uterine smooth muscle (UtSMC) and normal uterine myometrial (hUM) cells were also suppressed by AHE-ea. Two phytosterols, stigmasterol and ß-sitosterol, were identified from AHE-ea fraction. Mice treated with AHE-ea and stigmasterol alone demonstrated reduced diethylstilbestrol/medroxyprogesterone 17-acetate (DES/MPA)-induced uterine myometrial hyperplasia, which is the critical step for the development of leiomyoma. Taken together, our results suggest that the AHE-ea fraction could be considered as a natural plant-based medicine in the prevention or treatment of uterine leiomyoma growth.

Weight change and risk of uterine leiomyomas: Korea Nurses' Health Study.

OBJECTIVE: This study examined the associations between anthropometric measures and uterine leiomyomas. METHODS: This study included a total of 5,062 women (median age of 35.5 years) who had experienced pregnancy and, of these women, 210 reported a diagnosis of uterine leiomyomas within the past 2 years prior to baseline in the Korea Nurses' Health Study. Participants were asked about their anthropometric factors. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression models. RESULTS: Mean body mass index (BMI) was 21.8 kg/m2 among non-cases. An increase in weight from the age of 18 years to the present was associated with increased risk of uterine leiomyomas (p for trend = .002); compared to women whose weight remained stable, the multivariate ORs (95% CIs) were 1.84 (1.22-2.76) for weight gain of 5-10 kg and 2.00 (1.25-3.20) for weight gain of more than 10 kg since age 18. A similar pattern was observed when the analysis was limited to women with a BMI of 18.5-25 kg/m2. Current weight was associated with higher odds of uterine leiomyomas. No associations were found for body size in childhood or in adolescence, weight at age 18, current BMI, or current body size. CONCLUSIONS: Weight gain in adulthood was associated with increased risk of uterine leiomyomas in Korean women, even in those with normal weight.

Effects of liver depression and psychological stress on human uterine leiomyoma cells by an AR-cAMP-PKA signal transduction pathway.

OBJECTIVE: Based on the emotional theory of Traditional Chinese Medicine, and combined with the modern medicine theory of psychological stress, a research model of human uterine leiomyoma cells (ULM) was cultured in vitro to determine the effectiveness of adrenergic receptor (AR) agonists in human ULM cell growth. In addition, we studied the functional influence of "liver depression and psychological stress theory" on fibroid formation by intervening in the AR-cAMP-PKA signaling pathway. The intention was to establish a new method to prevent and cure fibroids through "liver depression and psychological stress theory" and provide an experimental basis for the Traditional Chinese Medicine emotional theory. MATERIALS AND METHODS: Primary human ULM cells were enriched by collagenase digestion. Immunohistochemistry and hematoxylin and eosin (HE) staining were used for cytological identification. Using this model, we studied intervention using specific AR agonists on ULM cells to observe the influence of "liver depression and psychological stress theory" on estrogen receptor (ER), progesterone receptor (PR), vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGF). RESULTS: Norepinephrine (NE) and epinephrine (E) are adrenergic receptor agonists. They promoted ULM cell proliferation and increased the levels of ER, PR, VEGF and FGF. In contrast, isoproterenol (ISO) inhibited ULM cell proliferation and decreased the levels of ER, PR, VEGF and FGF. The protein expression of cAMP and PKA in ULM cells was reduced and the levels of ER, PR, VEGF and FGF were increased when co-treatment with the α-AR blocker (phentolamine). The ß-AR blocker (metoprolol) displayed an opposite effect. CONCLUSIONS: AR agonists modulated ER, PR, VEGF and FGF levels in ULM cells in an AR-cAMP-PKA-dependent signaling pathways to influence fibroid occurrence and development.

Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: Focus on fibrosis.

Uterine fibroids (myomas or leiomyomas) are common benign tumors of reproductive aged women. Fibroids are clinically apparent in 20-50% of women, and cause abnormal uterine bleeding, abdominal pain and discomfort, pregnancy complications and infertility. Unfortunately, limited numbers of medical treatment are available but no effective preventive strategies exist. Moreover, the benefits of medical treatments are tempered by lack of efficacy or serious adverse side effects. Fibrosis has recently been recognized as a key pathological event in leiomyoma development and growth. It is defined by the excessive deposition of extracellular matrix (ECM). ECM plays important role in making bulk structure of leiomyoma, and ECM-rich rigid structure is believed to be a cause of abnormal bleeding and pelvic pain/pressure. Dietary phytochemicals are known to regulate fibrotic process in different biological systems, and being considered as potential tool to manage human health. At present, very few dietary phytochemicals have been studied in uterine leiomyoma, and they are mostly known for their antiproliferative effects. Therefore, in this review, our aim was to introduce some dietary phytochemicals that could target fibrotic processes in leiomyoma. Thus, this review could serve as useful resource to develop antifibrotic drugs for possible prevention and treatment of uterine fibroids.

Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target.

A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions. Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal women. They may occur in more than 70% of women, and approximately 25% of women show clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid management. Moreover, surgery negatively affects women's quality of life, and its associated cost appears to be expensive. The molecular mechanism of fibroids development and growth is not fully elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3, PI3K/AKT/mTOR, ERK 1/2 and ß-catenin are involved in the leiomyoma pathogenesis, indicating that they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce some potential dietary phytochemicals that could modulate those signaling pathways.

An Evidence-based Approach to the Medical Management of Fibroids: A Systematic Review.

Fibroids are the most common tumor of the female reproductive tract, but approved medical treatments are limited. Patients demand uterine-sparing treatments which preserve fertility and avoid surgery. We systematically reviewed PubMed and Cochrane databases from January 1985 to November 2015 for evidence-based medical therapies for fibroids in the context of disease prevention, treatment of early disease, treatment of symptomatic disease, and preoperative management. We identified 2182 studies, of which 52 studies met inclusion and exclusion criteria. Published data affirm the efficacy of multiple agents, which are promising avenues for the development of medical alternatives to surgery.

Use of depot medroxyprogesterone acetate and prevalent leiomyoma in young African American women.

STUDY QUESTION: Is use of depot medroxyprogesterone acetate (DMPA) a risk factor for or a protective factor against prevalent uterine leiomyoma? SUMMARY ANSWER: Ever use of DMPA was associated with a decreased risk (adjusted risk ratio (RR): 0.8, 95% confidence interval (CI): 0.6, 0.9) of prevalent leiomyoma in young African American women. WHAT IS KNOWN ALREADY: Although progesterone is associated with growth of leiomyoma, previous epidemiological studies have shown a protective association for DMPA use. These previous studies may have been biased by studying clinically diagnosed leiomyoma (DMPA may mask symptoms thus delaying diagnoses). STUDY DESIGN, SIZE, DURATION: Cross sectional analysis of baseline data from a cohort study of 1696 African American women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Community-based recruitment (e.g. letters, flyers, radio and TV announcements) were used to enroll African American women between 23 and 34 years old without a previous diagnosis of leiomyoma in the Metropolitan Detroit area. Extensive questionnaire data were used to determine DMPA use and screening ultrasound detected the presence of leiomyoma ≥0.5 cm in diameter. Relative risks with adjustment for covariates were calculated for the presence of leiomyoma based on ever use of DMPA as well as duration and recency of use. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 1696 volunteers who enrolled, 43% had used DMPA. Leiomyoma were detected in 17% of those who had ever used DMPA compared with 26% of those who had never used DMPA. The reduction in prevalence remained after adjustment for potential confounders and was highest among women who had used DMPA for more than 4 years (adjusted RR: 0.5, 95% CI: 0.3, 0.8). The reduction in risk was seen for women whose most recent use was up to 8 years prior to study enrollment. LIMITATIONS, REASONS FOR CAUTION: The use of cross-sectional data means that the timing of initial fibroid development is not known, so the temporality of the association is uncertain. However in this sample of young women, most fibroids were small, suggesting that DMPA exposure may have occurred before leiomyoma development. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in agreement with previous epidemiological studies, but protected from the bias inherent in the use of clinically diagnosed leiomyoma. Although further studies will be needed to elucidate the mechanism, use of DMPA as a contraceptive appears to provide long lasting protection against uterine leiomyoma. STUDY FUNDING/COMPETING INTERESTS: No competing interests. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, and in part by funds allocated for health research by the American Recovery and Reinvestment Act. TRIAL REGISTRATION NUMBER: N/A.

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review.

There is concern that morcellation of occult leiomyosarcomas during surgery to treat presumed myomas may substantially worsen patient outcome. We reviewed the existing medical literature to better understand whether such a risk was demonstrable and, if so, what the magnitude of that risk might be. We identified 4864 articles initially, of which 60 were evaluated in full. Seventeen were found to have outcomes information and are included in this review. Six studies addressed the question of whether morcellation of occult leiomyosarcomas resulted in inferior outcomes as compared with en bloc uterine and tumor removal. In these 6 studies, results suggested that en bloc removal may result in improved survival and less recurrence; however, the data are highly biased and of poor quality. There is no reliable evidence that morcellation, power or otherwise, substantially results in tumor upstaging. There is no evidence from these 17 studies that power morcellation differs in any way from other types of morcellation or even simple myomectomy insofar as patient outcome. Whether electromechanical morcellation poses a unique danger to the patient with occult leiomyosarcoma is an unanswered question and one clearly in need of more extensive investigation before conclusions are drawn and policies created.

Use of dietary phytochemicals to target inflammation, fibrosis, proliferation, and angiogenesis in uterine tissues: promising options for prevention and treatment of uterine fibroids?

Uterine leiomyomas (fibroids, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70-80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pressure on the bladder, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 6 billion dollars annually in the United States. Unfortunately, no long-term medical treatments are available. Dysregulation of inflammatory processes are thought to be involved in the initiation of leiomyoma and extracellular matrix deposition, cell proliferation, and angiogenesis are the key cellular events implicated in leiomyoma growth. In modern pharmaceutical industries, dietary phytochemicals are used as source of new potential drugs for many kinds of tumors. Dietary phytochemicals may exert therapeutic effects by interfering with key cellular events of the tumorigenesis process. At present, a negligible number of phytochemicals have been tested as therapeutic agents against fibroids. In this context, our aim was to introduce some of the potential dietary phytochemicals that have shown anti-inflammatory, antiproliferative, antifibrotic, and antiangiogenic activities in different biological systems. This review could be useful to stimulate the evaluation of these phytochemicals as possible therapies for uterine fibroids.

Paricalcitol, a vitamin d receptor activator, inhibits tumor formation in a murine model of uterine fibroids.

We examined the antitumor and therapeutic potentials of paricalcitol, an analog of 1,25-dihydroxyvitamin D3 with lower calcemic activity, against uterine fibroids using in vitro and in vivo evaluations in appropriate uterine fibroid cells and animal models. We found that paricalcitol has potential to reduce the proliferation of the immortalized human uterine fibroid cells. For the in vivo study, we generated subcutaneous tumors by injecting the Eker rat-derived uterine leiomyoma cell line (ELT-3) rat uterine fibroid-derived cell line in athymic nude mice supplemented with estrogen pellets. These mice were administered with vehicle versus paricalcitol (300 ng/kg/d) or 1,25-dihydroxyvitamin D3 (500 ng/kg/d) for 4 consecutive weeks, and the data were analyzed. We found that while both paricalcitol and 1,25-dihydroxyvitamin D3 significantly reduced fibroid tumor size, the shrinkage was slightly higher in the paricalcitol-treated group. Together, our results suggest that paricalcitol may be a potential candidate for effective, safe, and noninvasive medical treatment option for uterine fibroids.

Vitamin D and female fertility.

PURPOSE OF REVIEW: Apart from the well known effects of vitamin D on maintaining calcium homeostasis and promoting bone mineralization, there is some evidence suggesting that vitamin D also modulates human reproductive processes. We will review the most interesting and relevant studies on vitamin D and female fertility published over the past year. RECENT FINDINGS: In the past year, several observational studies reported a better in-vitro fertilization outcome in women with sufficient vitamin D levels (≥30 ng/ml), which was mainly attributed to vitamin D effects on the endometrium. One randomized controlled trial found an increased endometrial thickness in women with polycystic ovary syndrome (PCOS) receiving vitamin D during intrauterine insemination cycles. Further, vitamin D supplementation had a beneficial effect on serum lipids in PCOS women. Vitamin D treatment improved endometriosis in a rat model and increased vitamin D intake was related to a decreased risk of incident endometriosis. Vitamin D was also favorably associated with primary dysmenorrhea, uterine leiomyoma, and ovarian reserve in late reproductive aged women. SUMMARY: In women undergoing in-vitro fertilization, a sufficient vitamin D level (≥30 ng/ml) should be obtained. Vitamin D supplementation might improve metabolic parameters in women with PCOS. A high vitamin D intake might be protective against endometriosis.

Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth.

OBJECTIVE: To assess the effect of three WNT/ß-catenin pathway inhibitors-inhibitor of ß-catenin and TCF4 (ICAT), niclosamide, and XAV939-on the proliferation of primary cultures of human uterine leiomyoma cells. DESIGN: Prospective study of human leiomyoma cells obtained from myomectomy or hysterectomy. SETTING: University research laboratory. PATIENT(S): Women (n = 38) aged 27-53 years undergoing surgery. INTERVENTION(S): Adenoviral ICAT overexpression or treatment with varying concentrations of niclosamide or XAV939. MAIN OUTCOME MEASURE(S): Cell proliferation, cell death, WNT/-catenin target gene expression or reporter gene regulation, ß-catenin levels, and cellular localization. RESULT(S): Inhibitor of ß-catenin and TCF4, niclosamide, or XAV939 inhibit WNT/ß-catenin pathway activation and exert antiproliferative effects in primary cultures of human leiomyoma cells. CONCLUSION(S): Three WNT/-catenin pathway inhibitors specifically block human leiomyoma growth and proliferation, suggesting that the canonical WNT pathway may be a potential therapeutic target for the treatment of uterine leiomyoma. Our findings provide rationale for further preclinical and clinical evaluation of ICAT, niclosamide, and XAV939 as candidate antitumor agents for uterine leiomyoma.

Benign metastasizing leiomyoma. Case report and review of the literature.

Benign metastasizing leiomyoma (BML) is a rare clinical condition predominantly occurring in reproductive women with a history of uterine leiomyoma resection or hysterectomy. Oftentimes, it is easy to be misdiagnosed as a malignant tumor when nodules are found in multiple tissues. In order to raise clinicians' awareness of BML, we present a short review of the literature in combination with an unusual case.

Acetato de ulipristal 5 mg en el manejo de los miomas uterinos / No disponible

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