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.

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.

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.

Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata.

BACKGROUND: US black women have higher rates of uterine leiomyomata (UL) and lower intakes of fruit and vegetables than do white women. Whether fruit and vegetable intake is associated with UL in black women has not been studied. OBJECTIVE: We assessed the association of dietary intake of fruit, vegetables, carotenoids, folate, fiber, and vitamins A, C, and E with UL in the Black Women's Health Study. DESIGN: In this prospective cohort study, we followed 22,583 premenopausal women for incident UL (1997-2009). Diet was estimated by using food-frequency questionnaires in 1995 and 2001. Cox regression was used to derive incidence rate ratios (IRRs) and 95% CIs for the association between each dietary variable (in quintiles) and UL. RESULTS: There were 6627 incident cases of UL diagnosed by ultrasonography (n = 4346) or surgery (n = 2281). Fruit and vegetable intake was inversely associated with UL (≥4 compared with <1 serving/d; IRR: 0.90; 95% CI: 0.82, 0.98; P-trend = 0.03). The association was stronger for fruit (≥2 servings/d compared with <2 servings/wk; IRR: 0.89; 95% CI: 0.81, 0.98; P-trend = 0.07) than for vegetables (≥2 servings/d compared with <4 servings/wk: IRR: 0.97; 95% CI: 0.89, 1.05; P-trend = 0.51). Citrus fruit intake was inversely associated with UL (≥3 servings/wk compared with <1 serving/mo: IRR: 0.92; 95% CI: 0.86, 1.00; P-trend = 0.01). The inverse association for dietary vitamin A (upper compared with lower quintiles: IRR: 0.89; 95% CI: 0.83, 0.97; P-trend = 0.01) appeared to be driven by preformed vitamin A (animal sources), not provitamin A (fruit and vegetable sources). UL was not materially associated with dietary intake of vitamins C and E, folate, fiber, or any of the carotenoids, including lycopene. CONCLUSION: These data suggest a reduced risk of UL among women with a greater dietary intake of fruit and preformed vitamin A.

The effects of selenium supplementation on the spontaneously occurring fibroid tumors of oviduct, 8-hydroxy-2'-deoxyguanosine levels, and heat shock protein 70 response in Japanese quail.

Oxidative stress is known to be an important contributing factor in many chronic diseases. Spontaneously occurring benign oviduct leiomyomas 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. Since dietary intake of selenium has been associated with a reduced risk of a variety of human cancers, we investigated the effects of selenium supplementation on the development of leiomyomas in the Japanese quail. Potential mechanisms of action of selenium include its antioxidant properties and modulation of heat shock protein 70 (Hsp70); therefore, we measured levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane levels, and Hsp70 expression in tissue specimens obtained from the quails. One hundred and eighty quails (8 mo old) were assigned to 3 treatment groups consisting of 60 birds in each group. Birds were fed either a basal diet containing 0.048 mg Se per kg or the basal diet supplemented with 0.2 mg or 0.4 mg of selenium (Selenomax, yeast-bound l-selenomethionine, 60%) per kg of diet. The animals were sacrificed after 250 days, and the tumors were identified. Selenium supplementation did not affect the number of leiomyomas as compared to control subjects (P > 0.05). However, the tumors in selenium fed birds were smaller than those found in control birds (P = 0.01). Serum Se increased (P = 0.01), whereas MDA and 8-isoprostane, 8-OHdG concentrations decreased (P = 0.01) with selenium supplementation (P = 0.01). Selenium supplementation decreased Hsp70 in the tissue of birds. The results indicate that dietary supplementation with selenium reduces the size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail.

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.

Soybean isoflavones inhibit estrogen-stimulated gene expression in mouse uteri.

This study was performed to examine the inhibitory effects of soybean isoflavones on estrogen-stimulated gene expression of the uteri in ovarectomized mice. Especially when compared with the inhibitory effect of genistein and daidzein as aglycosides described in our previous report, subcutaneous administration of the glycoside genistin significantly decreased the levels of estradiol-17beta (E2)-induced expressions of c-jun, interleukin (IL)-1alpha and tumor necrosis factor (TNF)-alpha mRNAs (p < 0.005, p < 0.05 and p < 0.05, respectively) and seemingly proteins in the mice uteri, whereas the glycoside daidzin weakly inhibited E2-stimulated expressions of c-fos and IL-1alpha. Both genistin and daidzin seemed to have a weaker inhibitory effect than that of genistein and daidzein on the expression of estrogen-stimulated genes. It is suggested that those glycosides are naturally derived and generally absorbed from plant foods and might prevent E2-related endometrial carcinogenesis.

Endocrine disrupters and menopausal health.

Chemicals known to disrupt the endocrine system of animal models are assessed for their potential impact on the health of menopausal and postmenopausal women. These "endocrine disrupters" consist of two groups of compounds - man-made and naturally occurring. There is some evidence to suggest that the naturally occurring phytoestrogens, derived from plant material, may have some beneficial effects on menopausal symptoms and the risk of breast cancer, cardiovascular disease and osteoporosis. Further studies are required to confirm these possibilities. Some man-made environmental pollutants appear to increase the risk of breast cancer, although again the evidence is inconclusive. Mechanistic experiments indicate that these chemicals interact with oestrogen receptors and alter metabolism in a number of different ways, some of which may be important in postmenopausal women. Further investigation of the differences in mode of action between the man-made and the natural endocrine disrupters may lead to important insights into their effects on women's health.

Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium.

The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.

[Phytoestrogens in food--a review]. / Fitoestrogeny--wystepowanie w zywnosci.

The steroid hormone estrogen influences female and male reproductive system, 17-beta-oestradiol is the major human oestrogen. Phytoestrogens are naturally occurring oestrogens in many foods of plant origin. They are structurally and functionally similar to 17-beta-oestradiol or produce estrogenic effects. It is suggested that phytoestrogens could lower risk of diseases accompanied woman in meno- and postmenopausal stage. They are consider to decrease risk of breast, endometrial and ovarian cancer, osteoporosis, cardiovascular disease. This report presents the literature review on nutritious and health aspects connected with phytoestrogens. Generally authors confirm the possibility of beneficial health effects of phytoestrogens in humans.

Effects of Sasa Health, extract of bamboo grass leaves, on spontaneous mammary tumourigenesis in SHN mice.

Chronic treatment with Sasa Health, extract of bamboo grass leaves obtained by alkaline hydrolysis, in drinking water at the concentration of 0.044%-0.088% Fe-Chlorophyllin Na resulted in the significant inhibition of both development and growth of spontaneous mammary tumours in a high mammary tumour strain of SHN virgin mice. Limited treatment for 12 days in mice with palpable sizes of mammary tumours also markedly retarded the growth of the tumours. The end-bud formation and thymidylate synthetase activity of normal mammary glands were stimulated, but the formation of preneoplastic mammary hyperplastic alveolar nodules was inhibited by the treatment. Chronic ingestion of Sasa Health stimulated the excretion of urine components and decreased and increased the prolactin level and superoxide dismutase activity in serum, respectively. It showed no deleterious effects on food and water intake, body growth and any external appearance and all findings indicate that Sasa Health could be a promising agent for the protection and therapy of breast and other types of tumours.

Suppression of spontaneous development of uterine adenomyosis and mammary hyperplastic alveolar nodules by Chinese herbal medicines in mice.

The effects of traditional Chinese herbal remedies, Shakuyaku-kanzo-to (SKT) and Hachimijiou-gan (HJG), on the spontaneous development of uterine adenomyosis and mammary hyperplastic alveolar nodules (HAN) were examined in an experimental animal model using SHN strain of mice. Female mice were provided with the chow containing 1% of SKT or HJG during 25-150 days of age. At 150 days of age, SKT treatment showed significantly lower incidence of adenomyosis, and HJG treatment resulted in a significantly lower incidence of HAN when compared to a control chow containing no medicines. Long-term exposure to these herbal medicines affected little serum prolactin (PRL) level, estrous cycle, food intake and body growth. Thus, the present mouse data suggest that the oral administration of these herbal medicines is a useful tool for the treatment of uterine adenomyosis or mammary disorder such as cystic mastitis.