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.

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.

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 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.

Zinc picolinate in the prevention of leiomyoma in Japanese quail.

Epidemiologic studies suggest that zinc deficiency may be associated with increased risk of cancer. We investigated the effects of zinc picolinate supplementation on the development of leiomyomas, malondialdehyde (MDA), 8-isoprostane, 4-hydroxyalkenal (HAE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, and heat shock protein 70 (Hsp70) expression in Japanese quails. One hundred fifty quails (6 months old) were assigned to three treatment groups consisting of 50 birds in each group. Birds were fed either a basal diet or the basal diet supplemented with 30 mg or 60 mg of zinc/kg of diet. The animals were sacrificed after 350 days, and the tumors were identified. Zinc picolinate supplementation did not affect the number of leiomyomas compared to control birds (P > .05). However, the tumors in zinc-fed birds were smaller than those found in control birds (P = .01) Serum MDA, 8-isoprostane, and HAE levels were lower in the treatment groups than in the control group: MDA, 1.95 versus 0.93 micromol/L; 8-isoprostane, 108 versus 85 pg/mL; HAE, 1.55 versus 0.96 micromol/L (P = .01 for all three parameters). The concentrations of serum 8-OHdG, which is a marker of oxidative damage, in the groups were 28.5, 23.6, and 20.1 ng/mL, respectively (P = .01). Hsp70 expression was significantly decreased in zinc-treated birds (P < .01). The results indicate that dietary zinc picolinate supplementation reduces the growth of spontaneously occurring leiomyomas of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of zinc supplementation in the prevention and treatment of uterine leiomyoma in humans.

Chemoprevention of fibroid tumors by [-]-epigallocatechin-3-gallate in quail.

Spontaneous leiomyomas of the oviduct are common tumors of the Japanese quail (Coturnix coturnix japonica), and fibroid tumors in the laying hen are similar to human fibroid tumors with respect to estrogen and progesterone receptors. This makes the quail a good animal model for screening potential agents for that aid in the prevention and treatment of human myoma uteri. We have previously reported a decreased incidence of leiomyomas in the oviduct of Japanese quail with antioxidant supplementation, for example, lycopene and soy isoflavones. Most of the health benefits associated with green tea consumption is attributed to EGCG, one of 4 major catechins found in green tea. This study investigated the effects of epigallocatechin-3-gallate supplementation on the development of leiomyomas in the oviduct of Japanese quail. We also measured serum and tissue levels of malondialdehyde and TNF-alpha. One hundred eighty quail (8 months old) were assigned to 3 treatment groups consisting of 6 replicates of 10 quail in each group. Animals were fed either a basal diet (control group) or the basal diet supplemented with 200 or 400 mg of EGCG/kg of diet. The animals were euthanized at the end of the 12-month study period, and the tumors were characterized. Epigallocatechin gallate supplementation significantly decreased the number of leiomyomas as compared with the controls (P = .001). The tumors in the EGCG fed birds were smaller than those found in the control birds (P = .001). Serum and liver malondialdehyde and TNF-alpha concentrations decreased (P = .001) with EGCG supplementation. The results indicate that dietary supplementation with EGCG reduces the incidence and size of spontaneously occurring leiomyoma of the oviduct in Japanese quail. Clinical trials should be conducted to investigate the efficacy of EGCG supplementation in the prevention and treatment of uterine leiomyoma in humans.

Lycopene and other carotenoid intake in relation to risk of uterine leiomyomata.

OBJECTIVE: Carotenoids have antioxidant properties and have been associated with reduced risks of some cancers. We hypothesized that carotenoid intake may reduce the risk of diagnosed uterine leiomyoma (UL). STUDY DESIGN: We evaluated the associations between dietary carotenoids and risk of diagnosed UL in 82,512 premenopausal women aged 26-46 years in 1991 in the Nurses' Health Study II over 10 years of follow-up. Diet was assessed every 4 years with a validated food frequency questionnaire, and incidence of UL was assessed biennially by questionnaire. RESULTS: Total lycopene intake was not associated with diagnosed UL risk. Intake of beta-carotene was associated with slightly increased risks of diagnosed UL; this association was restricted to current smokers (for highest vs lowest quintile, relative risk = 1.36, 95% confidence interval 1.05 to 1.76; P(trend) = .003). CONCLUSION: Overall, our findings do not suggest that carotenoids reduce the risk of diagnosed UL. Among current smokers, high intake of beta-carotene may slightly increase risk of diagnosed UL.

Dietary tomato powder supplementation in the prevention of leiomyoma of the oviduct in the Japanese quail.

Spontaneous leiomyomas of the oviduct are common tumors of the Japanese Quail (Coturnix coturnix japonica), which makes it a good animal model for screening potential agents for testing in the prevention and treatment of human myoma uteri. We have previously reported a decreased incidence of leiomyomas in the oviduct of Japanese quail with lycopene supplementation. Although the major carotenoid in tomatoes is lycopene, tomatoes also contain other compounds, which may contribute to their health benefit. Therefore, in this study, we investigated the effects of tomato powder supplementation on the development of leiomyomas in the oviduct of Japanese quail. We also measured serum levels of malondialdehyde (MDA), carotenoids, and vitamins C, E, and A. A total of 150 quails (3 mo old) were assigned to 3 treatment groups consisting of 5 replicates of 10 birds in each group. Birds were fed either a basal diet (control group) or the basal diet supplemented with 25 g (Treatment I) or 50 g (Treatment II) of tomato powder (0.8 mg lycopene per g of tomato powder) per kg of diet. The animals were sacrificed after 365 days, and the tumors were identified. Tomato powder supplementation significantly decreased the number of leiomyomas as compared to control birds (P < 0.01). The tumors in tomato powder fed birds were smaller than those found in control birds (P < 0.01). Serum lycopene, lutein, zeaxantin, and vitamins C, E, and A increased (P = 0.01), whereas MDA concentrations decreased (P = 0.01) with tomato powder supplementation. No measurable lycopene could be detected in the serum of control birds, whereas a dose-dependent increase was observed in the serum of birds supplemented with tomato powder. The results indicate that dietary supplementation with tomato powder reduces the incidence and size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of tomato powder supplementation in the prevention and treatment of uterine leiomyoma in humans.

Lycopene supplementation prevents the development of spontaneous smooth muscle tumors of the oviduct in Japanese quail.

Leiomyomas (fibroids) are benign tumors of the uterus affecting millions of women. Spontaneous leiomyomas of the oviduct are common tumors of the Japanese quail (Coturnix coturnix japonica), which makes it a good animal model for screening potential agents for testing in the prevention and treatment of human myoma uteri. Because dietary intake of lycopene has been associated with a reduced risk of a variety of human cancers, we investigated the effects of lycopene supplementation on the development of leiomyomas in the oviduct of Japanese quail. We also measured serum levels of oxidative stress markers [malondialdehyde (MDA) and homocysteine], lycopene, vitamins C, E, and A, and tissue biomarkers Bcl-2 and Bax expression. One hundred twenty quails (6 mo old) were assigned to 3 treatment groups consisting of 4 replicates of 10 birds in each group. Birds were fed either a basal diet (group C) or the basal diet supplemented with 100 mg (group L1) or 200 mg (group L2) of lycopene per kilogram of diet. The animals were sacrificed after 285 days and the tumors were identified. Lycopene supplementation decreased the number of leiomyomas compared with control subjects (P=0.056). The tumors in lycopene-fed birds were smaller than those found in control birds (P=0.01). There were no significant differences in the expression of tissue Bcl-2 and Bax among the study groups. Serum vitamins C, E, and A increased (P=0.01), whereas MDA and homocysteine concentrations decreased (P=0.01) with lycopene supplementation. No measurable lycopene could be detected in the serum of control birds, whereas a dose-dependent increase was observed in the serum of lycopene-supplemented birds. The results indicate that dietary supplementation with lycopene reduces the incidence and size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of lycopene supplementation in the prevention and treatment of uterine leiomyoma in humans.