Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deﬁciency Abhishek Thakur 1, Subhash C

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

J Acupunct Meridian Stud 2016;9(3):109e117

Available online at www.sciencedirect.com Journal of Acupuncture and Meridian Studies

journal homepage: www.jams-kpi.com

REVIEW ARTICLE

Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deﬁciency Abhishek Thakur 1, Subhash C. Mandal 2, Sugato Banerjee 1,*

1 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India 2 Division of Pharmacognosy, Pharmacognosy and Phytotherapy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Available online 17 February 2016

Received: Sep 2, 2015 Abstract Revised: Jan 24, 2016 A predominant number of diseases affecting women are related to female hormones. In Accepted: Jan 28, 2016 most of the cases, these diseases are reported to be associated with menstrual problems. These diseases affect female reproductive organs such as the breast, uterus, and ovaries. KEYWORDS Estrogen is the main hormone responsible for the menstrual cycle, so irregular menstru- acupuncture; ation is primarily due to a disturbance in estrogen levels. Estrogen imbalance leads to estrogen; various pathological conditions in premenopausal women, such as endometriosis, breast natural compounds cancer, colorectal cancer, prostate cancer, poly cysts, intrahepatic cholestasis of pregnancy, osteoporosis, cardiovascular diseases, obesity, etc. In this review, we discuss common drug targets and therapeutic strategies, including acupuncture and compounds of natural origin, for the treatment of diseases caused by estrogen deﬁciency.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any me- dium, provided the original work is properly cited. * Corresponding author. Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India. E-mail: [email protected] (S. Banerjee).

pISSN 2005-2901 eISSN 2093-8152 http://dx.doi.org/10.1016/j.jams.2016.01.016 Copyright ª 2016, Medical Association of Pharmacopuncture Institute. 110 A. Thakur et al.

1. Introduction cardiovascular diseases, insulin resistance, and obesity [6,10]. Estrogen is also considered to be a morphogen for Estrogen, the primary female hormone, is synthesized in the uterus, ovary, mammary gland, prostate, lung, and the theca interna of the female ovary and varies throughout brain [11]. Recurrence in breast cancer after mastectomy the menstrual cycle. Follicle-stimulating hormone (FSH) and recurrence of endometriosis after total hysterectomy e also stimulates the production of estrogens by the gran- are not uncommon [12 14]. In such cancerous conditions, ulosa cells of the ovarian follicles and corpora lutea [1,2]. estrogen deprivation becomes a key therapeutic approach Estrogens are also synthesized in small amount in the [15]. breast, liver, adrenal glands, and fat cells. Estrogen is found to be at its highest level at the end of the follicular phase in a menstrual cycle, just before ovulation [3].It 2. Common drug targets in estrogen- promotes secondary sexual characters in females, such as dependent conditions breast development, and also helps maintain the thickening of the endometrium and prepares the uterine lining for Aromatase enzyme is responsible for the synthesis of es- implantation of the fertilized ovary [4,5]. Such estrogen trogens through conversion of androgens into estrogens by a dominance can start early in a woman’s menstrual history. process called aromatization [14,15]. This leads to an in- Long-term exposure to estrogen has been associated with crease in the rate of production of estrogen, which pro- the development of breast cancer. Estrogen may contribute motes estrogen-dependent diseases. This enzyme is to the development of cancer in an estrogen receptor (ER)- expressed in high concentrations in the placenta and the dependent or ER-independent manner [6,7]. The ER- granular cells of ovarian follicles. This enzyme is also pre- dependent mechanism states that estrogen primarily acts sent in several nonglandular tissues such as endometrial on ER alpha, which is a transcription factor and mediates tissue, breast cancer tissue, normal breast tissue, subcu- DNA synthesis and cellular proliferation. While some cells taneous fat, muscle, liver, and brain [16]. It is an anticancer may use different mechanisms to metabolize and deacti- target by compounds inhibiting the action of the enzyme in vate different estrogens (estradiol and estrone) resulting in postmenopausal women [13,17,18]. Estrogen-dependent the generation of an intermediate reactive oxygen species, diseases can be treated more effectively with new third- which may damage DNA and eventually lead to cancer [8]. generation aromatase inhibitors. The third-generation Aromatase, which may be localized in breast cancer aromatase inhibitors are available in preparations such as tissue, endometriosis, and uterine ﬁbroids, is responsible letrozole, anastrazole, vorazole, etc. [17,19]. Letrozole is for converting androgens (androstenedione and testos- considered to be the most promising aromatase inhibitor, as terone) into estrogens (estrone and estradiol), and for it has been studied that patients on letrozole have lower promoting cancerous growth and proliferation [8,9]. These plasma estrogen levels than those on other third-generation conditions may be dependent on the rising and falling of agents [20] (Fig. 1). estrogen waves during each menstrual cycle [6]. Estrogen is ER antagonists bind to ERs and inhibit the action of es- a hormone whose imbalance is responsible not only for trogen. ERs are available as homodimers of alpha and beta reproductive disorders, but also for different types of subunits (Fig. 2). ER alpha antagonist has shown resistance cancer. It may also contribute toward the development of in treating estrogen-dependent cancer for a prolonged lupus erythematosus, osteoporosis, Alzheimer’s disease, period of time [21]. Recent studies provide an important

Figure 1 Androgen bound to enzyme aromatase at its active binding site. Natural Estrogen Modulators 111

Figure 2 Estrogen bound to estrogen receptor a at its active binding site. interface to study the role of ER beta for estrogen- shown to interact with ERs. AhR may inhibit estrogen dependent tumors [22]. Among these estrogen antago- signaling by the activation of AhR/aryl hydrocarbon nuclear nists, ethinyl estradiol is used in preparations such as ovral- translocator heterodimer; by binding to an inhibitory L and novelon. Compounds of natural origin include xenobiotic response element in ER target genes; by genistein, which may act on both ER alpha and ER beta silencing coactivators, i.e., aryl hydrocarbon nuclear (Fig. 3). Commonly used drugs in this patient subgroup are translocator; by increasing proteasomal degradation of ER; clomifene and zuclomifene, which have found greater and by altering estrogen synthesis or metabolism [24]. acceptance [23]. Clomifene and zuclomifene are widely Several natural and synthetic agonists have been identified used estrogen antagonists that may control estrogen levels for this receptor. The first agonist to be identified was a during menstrual cycle. synthetic one; thereafter, many natural ligands were Aryl hydrocarbon receptor (AhR) is a ligand-mediated identified, including tryptophan, tetrapyrroles, and arach- transcription factor [24]. The AhR pathway has been idonic acid [25]. Although the role of natural compounds

Figure 3 Natural estrogen modulator (genistein) bound to estrogen receptor a at its active binding site. 112 Table 1 Natural estrogen modulators. 1. Genistein Glycine max Isoflavone Genistein may act by binding to estrogen receptors (a & b). [36] 2. Daidzein G. max Daidzein competes with endogenous estrogens binding with [38] 3. Equol G. max human recombinant estrogen receptor b & consequently [36] prevent their activity. 4. Luteolin Terminalia chebula Flavone Luteolin competes with endogenous estrogens binding with [36] human recombinant estrogen receptor b & consequently prevent their activity. 5. Chrysin Passiflora caerulea, Passiflora Chrysin performs potent inhibition of aromatase with [38] incarnata, Oroxylum indicum IC50 of 2.6 mM. 6. Quercetin Various fruits, vegetables, & grains Quercetin interacts with Type II estrogen-binding sites & inhibits [39] cell proliferation. 7. Kaempferol Apples, grapefruit, tea These have been found to bind weakly to the human recombinant [37] estrogen receptor b, thus preventing cell proliferation 8. Apigenin Various fruits & vegetables High doses of apigenin block ERa mobility & transcriptional activity, [43] & induce degradation of ERa & its coactivator AIB1. However, it may act via ERa-independent pathway as a kinase inhibitor. 9. 8-Prenyl Humulus lupulus Prenyl It has been shown to reduce hot flushes by binding to both ERa [40,41] naringenin flavonoid &ERb, but have higher affinity for ERa. 10. Naringenin Citrus paradisi Flavanone Studies have shown estrogen antagonist activity of this drug for [42] estrogen-sensitive cells. Have higher binding affinity for ERb than for ERa. 11. Enterodiol They are classified as mammalian Lignan Enterodiol acts as a protective agent for breast & prostate cancer [44e46] 12. Enterolactone phytoestrogens. They are synthesized by by inhibiting the aromatase enzyme, competing with estrogen for bacteria in colon from pinoresinol, Type II estrogen receptor, and inducing sex hormone-binding globulin. lariciresinol, secoisolariciresinol, matairesinol, hydroxymatairesinol, syringaresinol, & sesamin mostly found in flax seed & sesame seed 13. Resveratrol Skin of grapes, blueberries, raspberries, & Stilbenes Some studies states that it has higher transcriptional activity for [35,47,48] mulberries ERb than for ERa. Others state that it acts as an antagonist for ERa but not for ERb. Some studies have shown resveratrol as an aromatase inhibitor (IC50 2.5 mM) both by competitive & by noncompetitive inhibition. Moreover, this drug has been shown to induce apoptosis through AhR. 14. Indole-3- Cruciferous vegetables Indole Studies have shown that this drug does not bind to ERa &ERb. [49] carbinol derivative Rather, it triggers aryl hydrocarbon (AhR)-dependent degradation of ERa. Thus, degradation of ERa plays a significant role in inhibiting proliferation of estrogen-dependent tumor cells.

15. Ellagic acid Quercus alba, Quercus robur, Myriophyllum Polyphenol Ellagic acid may act as a selective estrogen receptor modulator. [50] al. et Thakur A. spicatum, Phellinus linteus It possesses little action on ERa while potently antagonizing ERb. 16. Gallic acid Q alba, Q. robur, Caesalpinia mimosoides Phenolic acid Studies on gallic acid, a natural phenolic acid found in plants, [50] have shown that it possesses higher affinity for ERb with an IC50 value of 100.3 mM. aua srgnModulators Estrogen Natural 17. Punicic acid Punica granatum Poly It has been shown to possess an estrogen-inhibiting activity, [51] unsaturated with IC50 values of 7.2 mM & 8.8 mMatERa &ERb, respectively. fatty acid 18. Delphinidin-3- Blackcurrant, blueberry, Anthocyanin Studies have shown that this chemical moiety possesses better [52] glucoside huckleberry, & bilberry leaves binding affinity for ERb with an IC50 value of 63.2 mM. For ERb, they have shown twofold more potency than gallic acid in spite of similar hydroxylation pattern at ring B. 19. Pelargonidin-3- Pomegranate, strawberry, & purple corn Belonging to anthocyanin class, it has shown affinity for both ERs, [52] glucoside but higher affinity for ERa (IC50 Z 61.3 mM) than for ERb (IC50 Z 93.0 mM). 20. Peonidin-3- Grapes & berries, red wine, red Studies have shown that this compound possesses affinity only [52] glucoside onion, & purple corn for ERa with an IC50 value of 64.4 mM. 21. Pelargonidin Pelargonium zonale, Anagallis monelli, Aglycone Studies have shown that this aglycone anthocyanin possess [53,54] Philodendron bipinnatifidum anthocyanin higher affinity for ERa as compared with ERb. SAR studies have shown that the presence of a 2-OH group at B ring decreases its affinity. Among all aglycone anthocyanins, pelargonidin has shown the highest affinity for ERa with an IC50 value of 6.8 mM. 22. Delphinidin Plants in the genera Viola & Delphinium Delphinidin shows higher affinity for ERa than for ERb. Delphinidin [54] has been shown to possess second highest affinity, after pelargonidin, for ERa with an IC50 value of 10.4 mM. 23. Cyanidin Different types of red berries Cyanidin possesses higher affinity for ERa as compared with [53,54] ERb, with an IC50 value of 10.4 mM for ERa. 24. Coumestrol Soybeans, Brussels sprouts, spinach, Coumestane Coumestrol has been shown to alleviate the conversion [55] & a variety of legumes of [3H]-estrone to [3H]-estradiol in vitro by inhibiting the enzyme 17b-hydroxysteroid oxidoreductase Type 1 in a dose-dependent manner.

AhR Z aryl hydrocarbon; ER Z estrogen receptor; IC50 Z Half maximal inhibitory concentration; SAR Z Structural-activity relationship. 113 114 A. Thakur et al. targeting estrogen-dependent diseases is unclear, in some studies phthalates have shown an interaction with ERs via AhR [26]. Studies have shown that people treated with drugs targeting estrogen-dependent diseases via AhR have less chance of developing osteoporosis [27]. Further studies on this receptor are needed, so that a potent AhR agonist can be formulated for targeting estrogen-dependent diseases [28].

3. Natural compounds as potential therapeutics

Flavonoids, primarily known for their antioxidant properties, have also shown antiestrogenic effect for the first time in sheep, which leads to infertility [29]. Some studies have shown that flavonoids may bind and activate ERs. Flavo- noids have been classified into six classes: flavonols, flavones, flavanols, flavanonols, flavanones, and isoflavones [30]. Among all flavones, isoflavones have been shown to possess the highest antiestrogenic activity. Flavanones and flavones have been shown to possess better antiestrogenic activity as compared with flavans. Studies have shown the importance of 6, 7, or 4 hydroxy group in flavones for estrogenic activity [31]. Coumestanes are a class of natural phytoestrogen found in a variety of food sources, including peas, beans, sprouts, etc. Coumestanes have been shown to have antiestrogenic propertiesdthey possess specific binding affinity for ER beta. To explore their antiestrogenic property, many chemical entities similar to coumestane class were synthesized and isolated. Among them cou- mesterol has shown more specific antiestrogenic affinity for ER beta [32]. Lignans, one of the important phytoestrogens obtained from dietary sources (flaxes and cereals), have been reported to possess antitumor activity against estrogen- dependent cancers. It is believed that lignans mimic estrogen and bind to ERs, thus preventing the action of endogenous estrogen. Moreover, studies also state that when phytoestrogens are consumed, the endogenous estrogen is flushed out of the body, adding to the antiestrogenic activity of phytoestrogens [33,34]. Stilbenes are diarylethylene hydrocarbons existing in two possible isomers, cis and trans. Many stilbenoids are present in plants, and between the two isoforms, trans possess greater antiestrogenic activity. Many synthetic drugs such as diethylstilbestrol, fosfestrol, and dienestrol have been designed on the basis of the trans isoform. Some natural stilbenes include pterostilbene and resveratrol [35]. A list of estrogen-modulating natural compounds and their mechanisms of action are listed in Table 1, while their chemical structures are shown in Fig. 4.

4. Acupuncture for estrogen-associated conditions Figure 4 Structures of natural compounds with estrogen- modulating properties. Premenopause and menopause may be associated with mood swings and minor memory deficit, which are associated with a low estrogen level. Although hormone Natural Estrogen Modulators 115 replacement therapy may improve the condition up to a may have a significant therapeutic impact on estrogen- and certain extent, there are other problems also [56]. Recent ER-associated diseases, which is required to be explored reports have shown certain acupuncture protocol may treat further. menopausal syndrome and subsequently improve memory [58,59]. The treatment is also claimed to alter plasma estradiol levels [57]. Acupuncture has also been shown to 5. Conclusion improve learning and memory by increasing brain estrogen levels in rats [58,59]. In a study comparing the effects of Here, we review the effect of different natural estrogenic acupuncture and estrogen on the frequency of hot flushes modulators as well as acupuncture against these patho- suggest that electroacupuncture may significantly reduce logical conditions. Acupuncture shows little adverse ef- the frequency of hot flushes. Although estrogen therapy fects. Some of the discussed natural compounds are may be more effective than acupuncture in reducing hot approved by the United States Food and Drug Administra- flushes, acupuncture therapy has limited side effects as tion as therapeutic agents for other diseases and thus may compared with estrogen therapy [60]. Vasomotor symptoms be readily used, while others, after appropriate toxicolog- are common among the group of women suffering from ical screening, may eventually develop into new thera- breast cancer who are undergoing antiestrogen therapy, so peutics for estrogen-dependent diseases. it becomes extremely difficult to treat such a group of patients. However, treatment of such a group of patients Disclosure statement for vasomotor symptoms associated with antiestrogen therapy with acupuncture appears to be effective and safe [61]. Repeated electroacupuncture stimulation at some The author declares to have no conflicts of interest and effective acupoints has also been reported to increase ER no financial interests related to the material of this expression and enhance estrogen levels in ovariectomized manuscript. animals, thus suggesting a long-term increase and normal- ization of Hypothalamic-pituitary-adrenal (HPA) axis References dysfunction [62,63]. Patients on acupuncture therapy showed decreased [1] Files JA, Ko MG, Pruthi S. Bioidentical hormone therapy. Mayo levels of FSH and luteinizing hormone in the serum, while Clin Proc. 2011;86:673e680. estradiol was increased. This in turn led to reduced anxiety, [2] Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone and improved menstruation and perimenopausal symptoms. therapy, a review. Menopause. 2004;11:356e367. The possible mechanism has been related to genes and [3] Nelson LR, Bulun SE. Estrogen production and action. JAm proteins associated with the PI3K (phosphoinositide 3-ki- Acad Dermatol. 2001;45:S116eS124. nase)/Akt/mTOR signaling pathway [64e66]. Han’s acu- [4] Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, et al. point nerve stimulator treatment could improve the clinical A role for estrogens in the male reproductive system. Nature. pregnancy rate in patients with a decreased ovarian reserve 1997;390:447e448. during in vitro fertilization and embryo transfer cycles by [5] The Sex Atlas. New York: The Continuum Publishing Company. Available at: http://www2rzhu-berlinde/sexology/GESUND/ increasing the antral follicle count and anti-Mu¨llerian hor- ARCHIV/ATLAS_EN/atlas.htm [Date accessed: August 25, mone levels and decreasing the estradiol level, FSH, and 2015]. FSH/luteinizing hormone ratio [67]. Polycystic ovary syn- [6] Deroo BJ, Korach KS. Estrogen receptors and human disease. J drome remains one of the most common causes of anov- Clin Invest. 2006;116:561e570. ulation in women of reproductive age, while nerve growth [7] Yue W, Yager JD, Wang JP, Jupe ER, Santen RJ. Estrogen factor has been associated with its pathogenesis. Electro- receptor-dependent and independent mechanisms of breast acupuncture treatment has been shown to partly reverse cancer carcinogenesis. Steroids. 2013;78:161e170. the nerve growth factor abundance, specifically in the [8] Health the Women. Available at: http://healthewomanorg/ ovaries [68,69]. Acupuncture can suppress abnormal in- 2009/06/12/exciting-news-for-endometriosis-aromatase- crease of body weight and decrease of plasma estrogen and inhibitors-and-ablation/ [Date accessed August 25, 2015]. [9] Serdar EB, Zhihong L, Gonca I, Sanober A, Masashi D, Bertan Y, estrin levels in a rat model of ovariectomy-induced osteo- et al. Regulation of aromatase expression in estrogen- porosis [70,71]. In human studies, therapeutic effect of responsive breast and uterine disease, from bench to treat- warm needle moxibustion on osteoporosis has been shown ment. Pharmacol Rev. 2005;57:359e383. to be better than that of oral caltrate with vitamin D2 [10] Brandenberger AW, Tee MK, Jaffe RB. Estrogen receptor alpha administration with a corresponding increase in estradiol (ER-alpha) and beta (ER-beta) mRNAs in normal ovary ovarian levels [72]. Acupuncture has also been shown to reduce serous cystadenocarcinoma and ovarian cancer cell lines, climacteric syndrome, associated with an increase in body down-regulation of ER-beta in neoplastic tissues. J Clin weight, by decreasing the estrogen level [73,74]. Evidence Endocrinol Metab. 1998;83:1025e1028. shows that acupuncture is responsible for an increase in [11] Heldring N, Pike A, Andersson S, Matthews J, Cheng G, ovarian granular cell layer P450 aromatase. P450 aromatase Hartman J, et al. Estrogen receptors, how do they signal and what are their targets. Am J Physiol. 2007;87:905e931. is an enzyme that has a role in estrogen synthesis and [12] Aromatase inhibitors. Breastcancer.org. Available at: http:// improved endometrial receptivity at the time of implanta- www.breastcancer.org/treatment/hormonal/aromatase_ tion [74,75]. Electroacupuncture of “Sanyinjiao” (SP6) and inhibitors [Date accessed August 15, 2015]. “Guanyuan” (CV4) may upregulate uterine and ovarian es- [13] Lewis-Wambi JS, Jordan VC. Estrogen regulation of apoptosis, trogens in rats by affecting the hypothal- how can one hormone stimulate and inhibit? Breast Cancer amusepituitaryeovarian axis [76e78]. Thus, acupuncture Res. 2009;11:206. 116 A. Thakur et al.

[14] Howell A, Dowsett M. Recent advances in endocrine therapy [34] Rice S, Whitehead SA. Phytoestrogens oestrogen synthesis and of breast cancer. BMJ. 1997;315:863e866. breast cancer. J Steroid Biochem Mol Biol. 2008;108:186e195. [15] Beatson GT. On the treatment of inoperable cases of carci- [35] Sanoh S, Kitamura S, Sugihara K, Fujimoto N, Ohta S. Estro- noma of the mamma, suggestions for a new method of genic activity of stilbene derivatives. J Health Sci. 2003;49: treatment with illustrative cases. Lancet. 1896;2:104e107. 359e367. [16] Stocco C. Tissue physiology and pathology of aromatase. [36] Patisaul HB, Jefferson W. The pros and cons of phytoes- Steroids. 2012;77:27e35. trogens. Front Neuroendocrinol. 2010;31:400e419. [17] Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, [37] Lund DT, Munson JD. Equol is a novel anti-androgen that in- Vogel CL. Anastrozole versus megestrol acetate in the treat- hibits prostate growth and hormone feedback. Biol Reprod. ment of postmenopausal women with advanced breast carci- 2004;70:1188e1195. noma, results of a survival update based on a combined [38] Kao YC, Zhou C, Sherman M, Laughton CA, Chen S. Molecular analysis of data from two mature phase III trials. Arimidex basis of the inhibition of human aromatase (estrogen synthe- Study Group. Cancer. 1998;83:1142e1152. tase) by flavone and isoflavone phytoestrogens, a site- [18] Thakur A, Timiri KA. Designing of potential new aromatase directed mutagenesis study. EHP. 1998;106:85e92. inhibitor for estrogen dependent diseases, a computational [39] Piantelli M, Maggiano N, Ricci R, Larocca LM, Capelli A, approach. WJPR. 2013;2:13e24. Scambia G, et al. Tamoxifen and quercetin interact with type [19] Lamb HM, Adkins JC. Letrozole. A review of its use in post- II estrogen binding sites and inhibit the growth of human menopausal women with advanced breast cancer. Drugs. melanoma cells. J Invest Dermatol. 1995;105:248e253. 1998;56:1125e1140. [40] Bowe J, Li XF, Jones JK, Heyerick A, Brain S, Milligan S, et al. [20] Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE. Influ- The hop phytoestrogen 8-prenyl naringenin reverses the ence of letrozole and anastrozole on total body aromatization ovariectomy-induced rise in skin temperature in an animal and plasma estrogen levels in postmenopausal breast cancer model of menopausal hot flushes. J Endocrinol. 2006;191: patients evaluated in a randomized cross-over study. J Clin 399e405. Oncol. 2002;20:751e757. [41] Possemiers S, Bolca S, Grootaert C, Heyerick A, Decroos K, [21] Normanno N, Di Maio M, De Maio E, De Luca A, de Matteis A, Dhooge W, et al. The prenylflavonoid isoxanthohumol from Giordano A, et al. Mechanisms of endocrine resistance and hops (Humulus lupulus L) is activated into the potent phyto- novel therapeutic strategies in breast cancer. Endocr Relat estrogen 8-prenylnaringenin in vitro and in the human intes- Cancer. 2005;12:721e747. tine. J Nutr. 2006;136:1862e1867. [22] Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, [42] Guo D, Wang J, Wang X, Luo H, Zhang H, Cao D, et al. Double Leitman DC. Estrogen receptor beta inhibits human breast directional adjusting estrogenic effect of naringin from Rhi- cancer cell proliferation and tumor formation by causing a G2 zoma drynariae (Gusuibu). J Ethnopharmacol. 2011;138: cell cycle arrest. Cancer Res. 2004;64:423e428. 451e457. [23] Huang ES, Miller WL. Estrogenic and anti-estrogenic effects of [43] Long X, Fan M, Bigsby MR, Nephew PK. Apigenin inhibits enclomiphene and zuclomiphene on gonadotropin secretion antiestrogen-resistant breast cancer cell growth through es- by ovine pituitary cells in culture. Endocrinology. 1983;112: trogen receptor-a-dependent and -independent mechanisms. 442e448. Mol Cancer Ther. 2008;7:2096e2108. [24] Matthews J, Gustafsson J. Estrogen receptor and aryl hydro- [44] Wang LQ. Mammalian phytoestrogens, enterodiol and enter- carbon receptor signaling pathways. Nucl Recept Signal. 2006; olactone. J Chromatogr B Analyt Technol Biomed Life Sci. 4:e016. 2002;777, 289e09. [25] Quintana FJ, Sherr DH. Aryl hydrocarbon receptor control of [45] Axelson M, Sjo¨vall J, Gustafsson BE, Setchell KD. Origin of adaptive immunity. Pharmacol Rev. 2013;65:1148e1161. lignans in mammals and identification of a precursor from [26] Hsieh TH, Tsai CF, Hsu CY, Kuo PL, Lee JN, Chai CY, et al. plants. Nature. 1982;298:659e660. Phthalates induce proliferation and invasiveness of estrogen [46] Heinonen S, Nurmi T, Liukkonen K, Poutanen K, Wa¨ha¨la¨ K, receptor-negative breast cancer through the AhR/HDAC6/c- Deyama T, et al. In vitro metabolism of plant lignans, new Myc signaling pathway. FASEB J. 2012;26:778e787. precursors of mammalian lignans enterolactone and enter- [27] Jordan VC. Selective estrogen receptor modulation, a per- odiol. J Agric Food Chem. 2001;49:3178e3186. sonal perspective. Cancer Res. 2001;61:5683e5687. [47] Bhat LPK, Lantvit D, Christov K, Mehta GR, Moon CR, Pezzuto MJ. [28] Safe S, McDougal A. Mechanism of action and development of Estrogenic and antiestrogenic properties of resveratrol in selective aryl hydrocarbon receptor modulators for treatment mammary tumor models. Cancer Res. 2001;61:7456e7463. of hormone-dependent cancers. Int J Oncol. 2002;20: [48] Wang Y, Lee KW, Chan FL, Chen S, Leung LK. The red wine 1123e1128. polyphenol resveratrol displays bilevel inhibition on aroma- [29] Bennetts HW, Underwood EJ, Shier FLA. Specific breeding tase in breast cancer cells. Toxicol Sci. 2006;92:71e77. problem of sheep on subterranean clover pasture in Western [49] Marconett NC, Sundar NS, Poindexter MK, Stueve RT, Australia. Austr Vet J. 1946;22:2e12. Bjedanes FL, Firestone LG. Indole-3cCarbinol triggers aryl [30] Marino M, Galluzzo P. Is there an answer? Are flavonoids hydrocarbon receptor-dependent estrogen receptor (ER)a agonist or antagonist of natural hormone 17b-estradiol? IUBMB protein degradation in breast cancer cells disrupting an ERa- Life. 2008;60:241e244. GATA3 transcriptional cross-regulatory loop. Mol Biol Cell. [31] Zand RSR, Jenkins DJA, Diamandis EP. Steroid hormone ac- 2010;21:1166e1177. tivity of flavonoids and related compounds. Breast Cancer Res [50] Papoutsi Z, Kassi E, Tsiapara A, Fokialakis N, Chrousos GP, Treat. 2000;62:35e49. Moutsatsou P. Evaluation of estrogenic/antiestrogenic ac- [32] Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van tivity of ellagic acid via the estrogen receptor subtypes der Saag PT, et al. Interaction of estrogenic chemicals and ERalpha and ERbeta. JAgricFoodChem. 2005;53: phytoestrogens with estrogen receptor beta. Endocrinology. 7715e7720. 1998;139:4252e4263. [51] Grossmann ME, Mizuno NK, Schuster T, Cleary MP. Punicic acid [33] Albini A, Rosano C, Angelini G, Amaro A, Esposito AI, is an omega-5 fatty acid capable of inhibiting breast cancer Maramotti S, et al. Exogenous hormonal regulation in breast proliferation. Int J Oncol. 2010;36:421e426. cancer cells by phytoestrogens and endocrine disruptors. Curr [52] Hidalgo M, Martin-Santamaria S, Recio I, Sanchez-Moreno C, Med Chem. 2014;21:1129e1145. de Pascual-Teresa B, Rimbach G, et al. Potential anti- Natural Estrogen Modulators 117

inflammatory anti-adhesive anti/estrogenic and angiotensin- [67] Zheng Y, Feng X, Mi H, Yao Y, Zhao Y, Li J, et al. Effects of converting enzyme inhibitory activities of anthocyanins and transcutaneous electrical acupoint stimulation on ovarian their gut metabolites. Genes Nutr. 2012;7, 295e06. reserve of patients with diminished ovarian reserve in in vitro [53] Schmitt E, Stopper H. Estrogenic activity of naturally occur- fertilization and embryo transfer cycles. J Obstet Gynaecol ring anthocyanidins. Nutr Cancer. 2001;41:145e149. Res. 2015;41:1905e1911. [54] Fang H, Tong W, Leming MS, Blair R. Structureeactivity re- [68] Stener-Victorin E, Lundeberg T, Waldenstro¨m U, Manni L, lationships for large diverse set of natural synthetic and envi- Aloe L, Gunnarsson S, et al. Effects of electro-acupuncture on ronmental estrogens. Chem Res Toxicol. 2001;14:280e294. nerve growth factor and ovarian morphology in rats with [55] Han D, Denison SM, Tachibana H, Yamada K. Relationship experimentally induced polycystic ovaries. Biol Reprod. 2000; between estrogen receptor-binding and estrogenic activities 63:1497e1503. of environmental estrogens and suppression by flavonoids. [69] Bai YH, Lim SC, Song CH, Bae CS, Jin CS, Choi BC, et al. Biosci Biotechnol Biochem. 2002;66:1479e1487. Electro-acupuncture reverses nerve growth factor abundance [56] Sherwin BB. Estrogen and memory in women: how can we in experimental polycystic ovaries in the rat. Gynecol Obstet reconcile the findings? Horm Behav. 2005;47:371e375. Invest. 2004;57:80e85. [57] Shen X, Du Y, Yan L, Xia Y, Yan H, Han G, et al. Acupuncture [70] Wei YF, Liu YL, Zhang SH, Wang ZO, Liu Y, Wang HC, et al. for treatment of climacteric syndromeda report of 35 cases. Effect of electroacupuncture on plasma estrin and bone J Tradit Chin Med. 2005;25:3e6. mineral density in ovariectomized rats. Zhen Ci Yan Jiu. 2007; [58] Tang X, Tang C, Xie H. Effect of ovariectomy on rat behavior 32:38e41. and hippocampal neuronal nitric oxide synthase and electro- [71] Ma J, Yun-guang H, Zhang DH. Effects of acupuncture on bone acupuncture intervention role. Sheng Wu Yi Xue Gong Cheng metabolism and serum estradiol level in ovariectomy-induced Xue Za Zhi. 2013;30:833e837. osteoporosis rats. Zhen Ci Yan Jiu. 2008;33:235e239. [59] Tang X, Tang CL, Xie HW, Song YE. Electroacupuncture im- [72] Zhao LH, Nong ZN, Zhong X, Pang Y, Liang JS, Li XD, et al. proves learning-memory of rats with low estrogen-induced Effects of warm needle moxibustion on bone mass density and cognitive impairment. Sheng Li Xue Bao. 2013;65:26e32. biochemical indexes of bone metabolism in patients of post- [60] Pinkerton JV, Stovall DW, Kightlinger RS. Advances in the menopausal osteoporosis. Zhongguo Zhen Jiu. 2008;28: treatment of menopausal symptoms. Womens Health. 2009;5: 897e900. 361e384. [73] Liu ZC, Sun FM, Yan RH. Clinical study on female obesity [61] Walker EM, Rodriguez AI, Kohn B, Ball RM, Pegg J, Pocock JR, complicated with climacteric syndrome treated by acupunc- et al. Acupuncture versus venlafaxine for the management of ture. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004;24:491e495. vasomotor symptoms in patients with hormone receptor- [74] Sun J, Jin C, Wu H, Zhao J, Cui Y, Liu H, et al. Effects of positive breast cancer: a randomized controlled trial. J Clin electro-acupuncture on ovarian P450arom, P450c17a and Oncol. 2010;28:634e640. mRNA expression induced by letrozole in PCOS rats. PLoS One. [62] Chen BY, Cheng LH, Gao H, Ji SZ. Effects of electro- 2013;8:e79382. acupuncture on the expression of estrogen receptor protein [75] Fu H, He Y, Gao Y, Man Y, Liu W, Hao H. Acupuncture on the and mRNA in rat brain. Acta Physiol Sin. 1998;50:495e500. endometrial morphology, the serum estradiol and progester- [63] Zhao H, Tian Z, Feng Y, Chen B. Circulating estradiol and hy- one levels, and the expression of endometrial leukaemia- pothalamic corticotrophin releasing hormone enhances along inhibitor factor and osteopontin in rats. Evid Based Comple- with time after ovariectomy in rats: effects of electro- ment Alternat Med. 2011;2011:606514. acupuncture. Neuropeptides. 2005;39:433e438. [76] Chen BY. Acupuncture normalizes dysfunction of hypothal- [64] Zhang Y, Yu B, Chen J, Zhao Z, Wang J, Huang F, et al. Effects of amicepituitaryeovarian axis. Acupunct Electrother Res. 1997; acupuncture on PI3K/Akt/mTOR signaling pathway in rats with 22:97e108. premature ovarian failure. Zhongguo Zhen Jiu. 2015;35:53e58. [77] Cheng K, Tian SL. Effects of preventive-electroacupuncture of [65] Chen Y, Fang Y, Yang J, Wang F, Wang Y, Yang L. Effect of “Guanyuan” (CV 4) and “Sanyinjiao” (SP 6) on hypothal- acupuncture on premature ovarian failure: a pilot study. Evid amusepituitaryeovary axis in ovariectomized rats. Zhen Ci Based Complement Alternat Med. 2014;2014:718675. Yan Jiu. 2012;37:15e19. [66] Wang F, Fang YG, Chen YR, Bai Y, Wu X, Liu BY. Acupuncture [78] Li Y, Xu L, Qin Z. Effects of electroacupuncture stimulation of for premature ovarian failure: a prospective cohort study. “Sanyinjiao” (SP 6) on hypothalamusepituitaryeovary axis in Zhongguo Zhen Jiu. 2014;34:653e656. perimenopausal rats. Zhen Ci Yan Jiu. 2014;39:198e201.