Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.

Estrogen Activity of OTC Topical Medications Containing Parabens Depends on Paraben Type and Concentration

Methylparaben, ethylparaben, and propylparaben are widely used as preservatives in food, cosmetics, and pharmaceutical products. Parabens are also known to bind the estrogen receptor and induce weak estrogen activity in laboratory bioassays. Many OTC topical medications contain one or more parabens as preservative ingredients. In this study, we surveyed the estrogen activity of extracts from OTC topical medications and tested the hypothesis that a combined threshold concentration of particular parabens is required to induce estrogen activity in human breast cancer cell bioassays. Ethanol extracts (1 gm:1 ml) were prepared from OTC topical medications containing parabens (including: Olay Quench Lotion, CeraVe Daily Moisturizing Lotion and Cortizon-10 Lotion). The estrogen agonist and antagonist activity of each extract was determined using the T47dkbluc estrogen reporter gene and the MCF-7 E3 estrogen responsive proliferation assays. The extracts from Olay Quench Lotion and CeraVe Daily Moisturizing Lotion induced estrogen agonist activity in the MCF-7 proliferation assay. The extract from the Cortizon-10 Lotion did not induce significant estrogen activity. The product ingredients of each OTC topical medications tested listed ethyl and propyl parabens while the Olay Quench Lotion also contained the least estrogenic paraben methylparaben. We propose that the estrogenic potential of OTC topical medications can be estimated with LC-MS analysis determination of paraben content and concentration. This study illustrates that measurable estrogen activity from OTC topical medications requires the presence of estrogenic parabens (ethyl and propyl) at total concentrations that exceed a threshold. Thus, estrogen activity depends on the type and concentration of paraben present in the OTC topical products. While the capacity for these OTC topical medications to induce estrogen activity in individuals using the products is unclear, consumers may benefit from more information about the paraben type and concentration present.

Natural Bioactive Compounds as Emerging Therapeutic Molecules against Breast Cancer: Emphasis on the Role of Phytoestrogens

Background:: Breast cancer is the leading form of cancer in women, which is also hormone-dependent. Depend-ing on the receptor expression these cancers are subdivided to different forms; among the receptors, estrogen, progesterone, and Her2 are important. Targeting breast cancer (BC) has been difficult due to their varied nature; however, various Phyto-compounds, especially those are having estrogen-like properties, has been proven to be effective. Objective:: The present review is aimed to provide a detailed description of various Phytocompounds inhibiting breast cancer proliferation and progression; emphasize has been given to the role of phytoestrogens with their molecular mechanism of action. Methods:: The data were collected from reputed databases such as PubMed/Medline, Web of Science, Science Direct, Eu-rekaselect etc. Data on the phytoestrogens were collected using individual names and “phytoestrogens” as keywords. Arti-cles published in journals, which are not indexed by Thomson Reuters (SCI/SCIE/ESCI) are omitted. Results:: Natural products are important drug candidates against multiple forms of breast cancer. In addition to the initiation and proliferation events, these molecules inhibit epithelial to mesenchymal transition (EMT) and metastasis of BC. Phy-toestrogens are an important class of compounds which has known estrogenic potential; studies have also indicated the anticancer potentials of these molecules in cell culture and animal models of BC. Conclusion:: Natural plant compounds, especially, phytoestrogens are promising anti-breast cancer agents by inducing cell cycle arrest, apoptosis and autophagy-mediated cell death. However, more clinical studies are necessary to up these mole-cules are commercial drug molecules.

Organophosphate Pesticide Exposure and Breast Cancer Risk: A Rapid Review of Human, Animal, and Cell-Based Studies

Background: Organophosphate pesticides (OPs) are one of the most commonly used classes of insecticides in the U.S., and metabolites of OPs have been detected in the urine of >75% of the U.S. population. While studies have shown that OP exposure is associated with risk of neurological diseases and some cancers, the relationship between OP exposure and breast cancer risk is not well understood. Methods: The aim of this rapid review was to systematically evaluate published literature on the relationship between OP exposure and breast cancer risk, including both epidemiologic and laboratory studies. Twenty-seven full-text articles were reviewed by searching on Pubmed, EMBASE, and Cochrane databases. Results: Some human studies showed that malathion, terbufos, and chlorpyrifos were positively associated with human breast cancer risk, and some laboratory studies demonstrated that malathion and chlorpyrifos have estrogenic potential and other cancer-promoting properties. However, the human studies were limited in number, mostly included agricultural settings in several geographical areas in the U.S., and did not address cumulative exposure. Conclusions: Given the mixed results found in both human and laboratory studies, more research is needed to further examine the relationship between OP exposure and breast cancer risk, especially in humans in non-agricultural settings.

Determination of the Estrogenic Activity of Coffee Extract Solutions Prepared from Capsule Coffee Using the BG1Luc4E2 Assay

Objectives Estrogenic chemicals (ECs) possess estrogenic activity (EA) which can have harmful effects on the reproductive system. Coffee is known to have estrogenic potency due to its natural phytoestrogens, but coffee prepared from plastic capsules (capsule coffee) may increase exposure to ECs and consequently increase EA, potentially increasing risk to reproductive health. The objective of this study was to determine the EA of capsule coffee extract solutions in vitro. Methods Six varieties of capsule coffee and two varieties of coffee prepared from whole beans using a stainless-steel French press were first brewed then concentrated and extracted. The BG1Luc4E2 assay was then conducted to determine the EA of the coffee extracts. The normalized EA (% RME2) of the coffee extracts was determined as the relative estrogenic potency compared to the maximum normalized EA of the positive control 17β-estradiol (set to 100 % RME2). EA was determined if at least one data point on the concentration-response curve was above 15% RME2 and confirmed via inhibition with the estrogen receptor antagonist ICI 182,780. The correlation between the EA estimated by the BG1Luc4E2 assay and the estrogenic potential (EEQ) was determined with Spearman's rank correlation coefficient. Results All eight coffee extract solutions tested positive for EA and results were confirmed by their complete inhibition with ICI. The level of EA for the six capsule coffee extracts ranged from 48 to 56 % RME2, while the level of EA for the two coffee varieties prepared from whole beans were 40 and 42 % RME2. There was a significant correlation between EA and EEQ was (ρ = 0.8857, P = 0.0333). Conclusions These results indicate that the EAs of capsule coffees were higher than that of coffee prepared from a plastic-free method and that the EA measured in an in vitro model was correlated with the calculated estrogenic potential of the coffee extract's EC contents. Future studies are warranted in in vivo models as well as in humans as tests of estrogenic potency in vitro do not necessarily predict the effects in living organisms. Funding Sources This study was supported by the National Institutes of Health.

Effect of methanolic extract of Amaranthus viridis leaves on reproductive functions in wistar female rats

Objective : The aim of this study is to determine the pharmacological effects and the estrogenic properties of Amaranthus viridis leaves on the reproductive function of animal model (female rat). Methods : Vaginal smears performed 9 days before treatment allowed to select female rats having alternated on two cycles a regularity. Thereafter, the selected rats were administered by gavage daily for 28 days taking care of smear every morning at 7am from the first day of treatment follow the evolution of the cycle. For this study 20 nulliparous rats, 2 months old, weighing between 120-150 g. The first group (control) was administered with olive oil and the other three batches received respectively the doses 200, 400 and 600 mg/kg of the methanolic extract of Amaranthus viridis. At the end of the 28-day treatment, ovary and uterine horn were removed, histological and hormonal parameters were studied for determine pharmacological effects of methanolic extract of Amaranthus viridis. Results : The extract caused a disturbances of the cycle according to the doses administered. Disturbances at doses 200 and 400 mg/kg PC are significant. The calculation of the total duration of the different phases of the cycle revealed very significant increases in the estrous phase (P<0.01) by 22.79 % and 17.13 % at the respective doses of 200 and 400 mg/kg b.w compared to control. Non-significant difference was recorded on FSH, LH and estradiol level. On progesterone level, administration of the methanolic extract showed a significant difference at dose of 600 mg/kg b.w compared to control. On histological structure of the ovary, the presence of active and degenerate corpus luteum, secondary follicles depending on the dose administered were recored. Conclusion : The results showed that the methanolic extract of Amaranthus viridis contain estrogenic substances or estrogen-like substances according to a dose-dependent mechanism, with high estrogenic potential at doses of 200 and 400 mg/kg b.w . Keywords: vaginal smears, Amaranthus viridis, methanolic extract, histology

Fenugreek seeds estrogenic activity in ovariectomized female rats

The estrogenic activities of fenugreek seeds (Trigonella foenum-graecum L.), widely used in traditional pharmacopoeia, are reflected in the uterus of ovariectomized female rats, with a slight increase in dry and wet weight, a thickening of the stroma and the uterine epithelium and the development of the endometrial glands. In the vagina, the estrogenic action is shown through an increase in the epidermal cell number and a tendency to keratinization, leading to vaginal opening. Furthermore, this estrogenic potential of fenugreek seeds is confirmed by the over-expression of progesterone receptors in the uterine tissues supporting possible interactions between phytoestrogens and estrogen receptors. Therefore, Fenugreek seeds may be capable of promoting the development of reproductive tissues of immature ovariectomized rats, and its estrogenic activity may take its action by holding phystoestrogens that interact with estrogen binding sites and activate the same estradiol-mediated cell signaling pathways. Thus, our results give added scientific support to the popular use of Fenugreek seeds as an alternative for several health problems such as fertility and menopause related disorders.

ANTIFERTILITY ACTIVITY AND CONTRACEPTIVE POTENTIAL OF THE HYDROALCOHOLIC RHIZOME EXTRACT OF TRILLIUM GOVANIANUM IN FEMALE WISTAR RATS

Objective: Trillium govanianum is used in several traditional containing steroids and sex hormones for the management of inflammation, menstrual disorders, sex-related disorders, and antiseptic. The present study was aimed to investigate the antifertility potential of hydroalcoholic rhizome extract of T. govanianum and to explore the possible mechanism of action. Methods: Anti-implantation activity of T. govanianum rhizome extract (125 and 250 mg/kg; p.o.) was performed in female Wistar rats with proven fertility, and its estrogenic/antiestrogenic effect was evaluated in ovariectomized females. 17-α-ethinylestradiol (1 μg/rat/day; s.c.) or plant extract was administered for 11 days after which animals were sacrificed. Percentage inhibition of implantation sites, serum estrogen levels, changes in body and uterus weight, and morphological alterations in the uterus and ovaries were evaluated. Results: T. govanianum treatment resulted in increased uterus weight and induced dose-dependent anti-implantation effect, with 100% implantation inhibition at 250 mg/kg dose. Anti-implantation effects of T. govanianum were associated with endometrial thickening and significantly elevated serum estrogen levels. Moreover, estrogenic/antiestrogenic studies revealed that T. govanianum possessed strong estrogenic effect; however, the effect was saturable. Conclusion: T. govanianum possesses antifertility activity which can be attributed to its strong estrogenic potential and uterine thickening. Moreover, it could find a clinical application as a safer and efficacious birth control herbal remedy.