Botanical Modulation of Menopausal Symptoms: Mechanisms of
                    Action?

Atieh Hajirahimkhan; Birgit M. Dietz; Judy L. Bolton

doi:10.1055/s-0032-1328187

Planta Medica, Table of Contents

Planta Med 2013; 79(07): 538-553
DOI: 10.1055/s-0032-1328187

Women's Health

Reviews

Georg Thieme Verlag KG Stuttgart · New York

Botanical Modulation of Menopausal Symptoms: Mechanisms of Action?

Atieh Hajirahimkhan

¹UIC/NIH Center for Botanical Dietary Supplements, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA

,

Birgit M. Dietz

¹UIC/NIH Center for Botanical Dietary Supplements, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA

,

Judy L. Bolton

¹UIC/NIH Center for Botanical Dietary Supplements, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA

› Author Affiliations

Abstract

Menopausal women suffer from a variety of symptoms, including hot flashes and night sweats, which can affect quality of life. Although it has been the treatment of choice for relieving these symptoms, hormone therapy has been associated with increased breast cancer risk leading many women to search for natural, efficacious, and safe alternatives such as botanical supplements. Data from clinical trials suggesting that botanicals have efficacy for menopausal symptom relief have been controversial, and several mechanisms of action have been proposed including estrogenic, progestogenic, and serotonergic pathways. Plant extracts with potential estrogenic activities include soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry. Botanicals with reported progestogenic activities are red clover, hops, yam, and chasteberry. Serotonergic mechanisms have also been proposed since women taking antidepressants often report a reduction in hot flashes and night sweats. Black cohosh, kudzu, kava, licorice, and dong quai all either have reported 5-hydroxytryptamine receptor 7 ligands or inhibit serotonin reuptake, therefore have potential serotonergic activities. Understanding the mechanisms of action of these natural remedies used for womenʼs health could lead to more efficacious formulations and to the isolation of active components which have the potential of becoming effective medications in the future.

Key words

botanicals - estrogen - isoflavones - menopause - progesterone - serotonin

Full Text

References

References
1 Roush K. Managing menopausal symptoms. Am J Nurs 2012; 112: 28-35
2 Ortmann O, Lattrich C. The treatment of climacteric symptoms. Dtsch Arztebl Int 2012; 109: 316-323
3 Aidelsburger P, Schauer S, Grabein K, Wasem J. Alternative methods for the treatment of post-menopausal troubles. GMS Health Technol Assess 2012;
4 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womenʼs Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333
5 Geller SE, Studee L. Botanical and dietary supplements for menopausal symptoms: what works, what does not. J Womens Health 2005; 14: 634-649
6 Pitkin J. Alternative and complementary therapies for the menopause. Menopause Int 2012; 18: 20-27
7 Wang XY, Nie GN, Yang HY, Zong LL. Chinese medicine for menopausal syndrome: current status, problems and strategies. Chin J Integr Med 2011; 17: 889-892
8 Taechakraichana N, Jaisamrarn U, Panyakhamlerd K, Chaikittisilpa S, Limpaphayom KK. Climacteric: concept, consequence and care. J Med Assoc Thai 2002; 85 (Suppl. 01) S1-S15
9 Overk CR, Yao P, Chadwick LR, Nikolic D, Sun Y, Cuendet MA, Deng Y, Hedayat AS, Pauli GF, Farnsworth NR, van Breemen RB, Bolton JL. Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). J Agric Food Chem 2005; 53: 6246-6253
10 Al-Nakkash L, Markus B, Batia L, Prozialeck WC, Broderick TL. Genistein induces estrogen-like effects in ovariectomized rats but fails to increase cardiac GLUT4 and oxidative stress. J Med Food 2010; 13: 1369-1375
11 Toh MF, Sohn J, Chen SN, Yao P, Bolton JL, Burdette JE. Biological characterization of non-steroidal progestins from botanicals used for womenʼs health. Steroids 2012; 77: 765-773
12 Powell SL, Godecke T, Nikolic D, Chen SN, Ahn S, Dietz B, Farnsworth NR, van Breemen RB, Lankin DC, Pauli GF, Bolton JL. In vitro serotonergic activity of black cohosh and identification of N(omega)-methylserotonin as a potential active constituent. J Agric Food Chem 2008; 56: 11718-11726
13 Chueh FS, Chang CP, Chio CC, Lin MT. Puerarin acts through brain serotonergic mechanisms to induce thermal effects. J Pharmacol Sci 2004; 96: 420-427
14 Ames MS, Hong S, Lee HR, Fields HW, Johnston WM, Kim DG. Estrogen deficiency increases variability of tissue mineral density of alveolar bone surrounding teeth. Arch Oral Biol 2010; 55: 599-605
15 Pelekanou V, Leclercq G. Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis. Int J Dev Biol 2011; 55: 869-878
16 Pastore MB, Jobe SO, Ramadoss J, Magness RR. Estrogen receptor-alpha and estrogen receptor-beta in the uterine vascular endothelium during pregnancy: functional implications for regulating uterine blood flow. Semin Reprod Med 2012; 30: 46-61
17 Nofer JR. Estrogens and atherosclerosis: insights from animal models and cell systems. J Mol Endocrinol 2012; 48: R13-R29
18 Krishnan V, Heath H, Bryant HU. Mechanism of action of estrogens and selective estrogen receptor modulators. Vitam Horm 2000; 60: 123-147
19 OʼDonnell E, Harvey PJ, Goodman JM, De Souza MJ. Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women. Am J Physiol Endocrinol Metab 2007; 292: E1401-E1409
20 Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA. Mechanisms of estrogen action. Physiol Rev 2001; 81: 1535-1565
21 Ellmann S, Sticht H, Thiel F, Beckmann MW, Strick R, Strissel PL. Estrogen and progesterone receptors: from molecular structures to clinical targets. Cell Mol Life Sci 2009; 66: 2405-2426
22 Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 2005; 19: 833-842
23 OʼLone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol Endocrinol 2004; 18: 1859-1875
24 Song RX, Santen RJ. Membrane initiated estrogen signaling in breast cancer. Biol Reprod 2006; 75: 9-16
25 Filardo EJ. Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem Mol Biol 2002; 80: 231-238
26 Prossnitz ER, Sklar LA, Oprea TI, Arterburn JB. GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci 2008; 29: 116-123
27 Shanle EK, Xu W. Selectively targeting estrogen receptors for cancer treatment. Adv Drug Deliv Rev 2010; 62: 1265-1276
28 Thomas C, Gustafsson JA. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 2011; 11: 597-608
29 Deroo BJ, Buensuceso AV. Minireview: Estrogen receptor-beta: mechanistic insights from recent studies. Mol Endocrinol 2010; 24: 1703-1714
30 Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998; 139: 4252-4263
31 Pike MC, Ross RK. Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer. Steroids 2000; 65: 659-664
32 Dave B, Wynne R, Su Y, Korourian S, Chang JC, Simmen RC. Enhanced mammary progesterone receptor-A isoform activity in the promotion of mammary tumor progression by dietary soy in rats. Nutr Cancer 2010; 62: 774-782
33 Scarpin KM, Graham JD, Mote PA, Clarke CL. Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl Recept Signal 2009;
34 Gronemeyer H, Meyer ME, Bocquel MT, Kastner P, Turcotte B, Chambon P. Progestin receptors: isoforms and antihormone action. J Steroid Biochem Mol Biol 1991; 40: 271-278
35 Aupperlee MD, Haslam SZ. Differential hormonal regulation and function of progesterone receptor isoforms in normal adult mouse mammary gland. Endocrinology 2007; 148: 2290-2300
36 Harduf H, Goldman S, Shalev E. Progesterone receptor A and c-Met mediates spheroids-endometrium attachment. Reprod Biol Endocrinol 2009;
37 Kariagina A, Aupperlee MD, Haslam SZ. Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology 2007; 148: 2723-2736
38 Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. Pathophysiology and treatment of hot flashes. Mayo Clin Proc 2002; 77: 1207-1218
39 Pearlstein T. Psychotropic medications and other non-hormonal treatments for premenstrual disorders. Menopause Int 2012; 18: 60-64
40 Nachtigall LE. Therapy: nonhormonal treatment of hot flashes – a viable alternative?. Nat Rev Endocrinol 2010; 6: 66-67
41 Kintscher U. Reuptake inhibitors of dopamine, noradrenaline, and serotonin. Handb Exp Pharmacol 2012; 209: 339-347
42 Taylor M. Complementary and alternative medicine preparations used to treat symptoms of menopause. Menopausal Med 2012; 20: S1-S8
43 Tsunoda N, Pomeroy S, Nestel P. Absorption in humans of isoflavones from soy and red clover is similar. J Nutr 2002; 132: 2199-2201
44 Oerter Klein K, Janfaza M, Wong JA, Chang RJ. Estrogen bioactivity in fo-ti and other herbs used for their estrogen-like effects as determined by a recombinant cell bioassay. J Clin Endocrinol Metab 2003; 88: 4077-4079
45 Nielsen IL, Williamson G. Review of the factors affecting bioavailability of soy isoflavones in humans. Nutr Cancer 2007; 57: 1-10
46 Mortensen A, Kulling SE, Schwartz H, Rowland I, Ruefer CE, Rimbach G, Cassidy A, Magee P, Millar J, Hall WL, Kramer Birkved F, Sorensen IK, Sontag G. Analytical and compositional aspects of isoflavones in food and their biological effects. Mol Nutr Food Res 2009; 53: S266-S309
47 McCarty MF. Isoflavones made simple – genisteinʼs agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 2006; 66: 1093-1114
48 Harris DM, Besselink E, Henning SM, Go VL, Heber D. Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells. Exp Biol Med 2005; 230: 558-568
49 Zhao L, Mao Z, Brinton RD. A select combination of clinically relevant phytoestrogens enhances estrogen receptor beta-binding selectivity and neuroprotective activities in vitro and in vivo . Endocrinology 2009; 150: 770-783
50 Muthyala RS, Ju YH, Sheng S, Williams LD, Doerge DR, Katzenellenbogen BS, Helferich WG, Katzenellenbogen JA. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem 2004; 12: 1559-1567
51 Jackson RL, Greiwe JS, Schwen RJ. Emerging evidence of the health benefits of S-equol, an estrogen receptor beta agonist. Nutr Rev 2011; 69: 432-448
52 Yuan JP, Wang JH, Liu X. Metabolism of dietary soy isoflavones to equol by human intestinal microflora–implications for health. Mol Nutr Food Res 2007; 51: 765-781
53 Atkinson C, Frankenfeld CL, Lampe JW. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med 2005; 230: 155-170
54 Shor D, Sathyapalan T, Atkin SL, Thatcher NJ. Does equol production determine soy endocrine effects?. Eur J Nutr 2012; 51: 389-398
55 Zhang EJ, Ng KM, Luo KQ. Extraction and purification of isoflavones from soybeans and characterization of their estrogenic activities. J Agric Food Chem 2007; 55: 6940-6950
56 Schmitt E, Dekant W, Stopper H. Assaying the estrogenicity of phytoestrogens in cells of different estrogen sensitive tissues. Toxicol In Vitro 2001; 15: 433-439
57 Onoda A, Ueno T, Uchiyama S, Hayashi S, Kato K, Wake N. Effects of S-equol and natural S-equol supplement (SE5-OH) on the growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice. Food Chem Toxicol 2011; 49: 2279-2284
58 Ju YH, Fultz J, Allred KF, Doerge DR, Helferich WG. Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice. Carcinogenesis 2006; 27: 856-863
59 Hwang CS, Kwak HS, Lim HJ, Lee SH, Kang YS, Choe TB, Hur HG, Han KO. Isoflavone metabolites and their in vitro dual functions: they can act as an estrogenic agonist or antagonist depending on the estrogen concentration. J Steroid Biochem Mol Biol 2006; 101: 246-253
60 Sakamoto T, Horiguchi H, Oguma E, Kayama F. Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem 2010; 21: 856-864
61 Sathyamoorthy N, Wang TT. Differential effects of dietary phyto-oestrogens daidzein and equol on human breast cancer MCF-7 cells. Eur J Cancer 1997; 33: 2384-2389
62 Chang EC, Charn TH, Park SH, Helferich WG, Komm B, Katzenellenbogen JA, Katzenellenbogen BS. Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol 2008; 22: 1032-1043
63 van Meeuwen JA, Korthagen N, de Jong PC, Piersma AH, van den Berg M. (Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture. Toxicol Appl Pharmacol 2007; 221: 372-383
64 Wober J, Weisswange I, Vollmer G. Stimulation of alkaline phosphatase activity in Ishikawa cells induced by various phytoestrogens and synthetic estrogens. J Steroid Biochem Mol Biol 2002; 83: 227-233
65 Kayisli UA, Aksu CA, Berkkanoglu M, Arici A. Estrogenicity of isoflavones on human endometrial stromal and glandular cells. J Clin Endocrinol Metab 2002; 87: 5539-5544
66 Cimafranca MA, Davila J, Ekman GC, Andrews RN, Neese SL, Peretz J, Woodling KA, Helferich WG, Sarkar J, Flaws JA, Schantz SL, Doerge DR, Cooke PS. Acute and chronic effects of oral genistein administration in neonatal mice. Biol Reprod 2010; 83: 114-121
67 Legette LL, Martin BR, Shahnazari M, Lee WH, Helferich WG, Qian J, Waters DJ, Arabshahi A, Barnes S, Welch J, Bostwick DG, Weaver CM. Supplemental dietary racemic equol has modest benefits to bone but has mild uterotropic activity in ovariectomized rats. J Nutr 2009; 139: 1908-1913
68 Boue SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE. Evaluation of the estrogenic effects of legume extracts containing phytoestrogens. J Agric Food Chem 2003; 51: 2193-2199
69 de Lima Toccafondo Vieira M, Duarte RF, Campos LM, Nunan Ede A. Comparison of the estrogenic potencies of standardized soy extracts by immature rat uterotrophic bioassay. Phytomedicine 2008; 15: 31-37
70 Allred CD, Allred KF, Ju YH, Goeppinger TS, Doerge DR, Helferich WG. Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis 2004; 25: 1649-1657
71 Hilakivi-Clarke L, Andrade JE, Helferich W. Is soy consumption good or bad for the breast?. J Nutr 2010; 140: 2326S-2334S
72 Dietz BM, Bolton JL. Anti-inflammatory botanical dietary supplements for womenʼs health: role in breast cancer prevention?. In: Kong T, , editor Inflammation and cancer: mechanisms and dietary approaches for cancer prevention. Boca Raton: CRC Press; in press
73 Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997; 138: 863-870
74 Piersen CE, Booth NL, Sun Y, Liang W, Burdette JE, van Breemen RB, Geller SE, Gu C, Banuvar S, Shulman LP, Bolton JL, Farnsworth NR. Chemical and biological characterization and clinical evaluation of botanical dietary supplements: a phase I red clover extract as a model. Curr Med Chem 2004; 11: 1361-1374
75 Booth NL, Overk CR, Yao P, Burdette JE, Nikolic D, Chen SN, Bolton JL, van Breemen RB, Pauli GF, Farnsworth NR. The chemical and biologic profile of a red clover (Trifolium pratense L.) phase II clinical extract. J Altern Complement Med 2006; 12: 133-139
76 Hsu JT, Hung HC, Chen CJ, Hsu WL, Ying C. Effects of the dietary phytoestrogen biochanin A on cell growth in the mammary carcinoma cell line MCF-7. J Nutr Biochem 1999; 10: 510-517
77 Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol 1993; 45: 399-405
78 Fokialakis N, Alexi X, Aligiannis N, Siriani D, Meligova AK, Pratsinis H, Mitakou S, Alexis MN. Ester and carbamate ester derivatives of Biochanin A: synthesis and in vitro evaluation of estrogenic and antiproliferative activities. Bioorg Med Chem 2012; 20: 2962-2970
79 Halabalaki M, Alexi X, Aligiannis N, Lambrinidis G, Pratsinis H, Florentin I, Mitakou S, Mikros E, Skaltsounis AL, Alexis MN. Estrogenic activity of isoflavonoids from Onobrychis ebenoides . Planta Med 2006; 72: 488-493
80 Zoechling A, Reiter E, Eder R, Wendelin S, Liebner F, Jungbauer A. The flavonoid kaempferol is responsible for the majority of estrogenic activity in red wine. Am J Enol Viticult 2009; 60: 223-232
81 Burdette JE, Liu J, Lantvit D, Lim E, Booth N, Bhat KP, Hedayat S, Van Breemen RB, Constantinou AI, Pezzuto JM, Farnsworth NR, Bolton JL. Trifolium pratense (red clover) exhibits estrogenic effects in vivo in ovariectomized Sprague-Dawley rats. J Nutr 2002; 132: 27-30
82 Overk CR, Guo J, Chadwick LR, Lantvit DD, Minassi A, Appendino G, Chen SN, Lankin DC, Farnsworth NR, Pauli GF, van Breemen RB, Bolton JL. In vivo estrogenic comparisons of Trifolium pratense (red clover), Humulus lupulus (hops), and the pure compounds isoxanthohumol and 8-prenylnaringenin. Chem Biol Interact 2008; 176: 30-39
83 Zhang D, Ren Y, Dai S, Liu W, Li G. [Isoflavones from vines of Pueraria lobata]. Zhongguo Zhong Yao Za Zhi 2009; 34: 3217-3220
84 Delmonte P, Perry J, Rader JI. Determination of isoflavones in dietary supplements containing soy, Red Clover and kudzu: extraction followed by basic or acid hydrolysis. J Chromatogr A 2006; 1107: 59-69
85 Park EK, Shin J, Bae EA, Lee YC, Kim DH. Intestinal bacteria activate estrogenic effect of main constituents puerarin and daidzin of Pueraria thunbergiana . Biol Pharm Bull 2006; 29: 2432-2435
86 Nakamura K, Nishihata T, Jin JS, Ma CM, Komatsu K, Iwashima M, Hattori M. The C-glucosyl bond of puerarin was cleaved hydrolytically by a human intestinal bacterium strain PUE to yield its aglycone daidzein and an intact glucose. Chem Pharm Bull 2011; 59: 23-27
87 Cherdshewasart W, Traisup V, Picha P. Determination of the estrogenic activity of wild phytoestrogen-rich Pueraria mirifica by MCF-7 proliferation assay. J Reprod Dev 2008; 54: 63-67
88 Cherdshewasart W, Cheewasopit W, Picha P. The differential anti-proliferation effect of white (Pueraria mirifica), red (Butea superba), and black (Mucuna collettii) Kwao Krua plants on the growth of MCF-7 cells. J Ethnopharmacol 2004; 93: 255-260
89 Matsumura A, Ghosh A, Pope GS, Darbre PD. Comparative study of oestrogenic properties of eight phytoestrogens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol 2005; 94: 431-443
90 Boonchird C, Mahapanichkul T, Cherdshewasart W. Differential binding with ERalpha and ERbeta of the phytoestrogen-rich plant Pueraria mirifica . Braz J Med Biol Res 2010; 43: 195-200
91 Gomuttapong S, Pewphong R, Choeisiri S, Jaroenporn S, Malaivijitnond S. Testing of the estrogenic activity and toxicity of Stephania venosa herb in ovariectomized rats. Toxicol Mech Methods 2012; 22: 445-457
92 Malaivijitnond S, Chansri K, Kijkuokul P, Urasopon N, Cherdshewasart W. Using vaginal cytology to assess the estrogenic activity of phytoestrogen-rich herb. J Ethnopharmacol 2006; 107: 354-360
93 Sookvanichsilp N, Soonthornchareonnon N, Boonleang C. Estrogenic activity of the dichloromethane extract from Pueraria mirifica . Fitoterapia 2008; 79: 509-514
94 Urasopon N, Hamada Y, Cherdshewasart W, Malaivijitnond S. Preventive effects of Pueraria mirifica on bone loss in ovariectomized rats. Maturitas 2008; 59: 137-148
95 Malaivijitnond S, Tungmunnithum D, Gittarasanee S, Kawin K, Limjunyawong N. Puerarin exhibits weak estrogenic activity in female rats. Fitoterapia 2010; 81: 569-576
96 Malaivijitnond S. Medical applications of phytoestrogens from the Thai herb Pueraria mirifica . Front Med 2012; 6: 8-21
97 Salter S, Brownie S. Treating primary insomnia – the efficacy of valerian and hops. Aust Fam Physician 2010; 39: 433-437
98 Blumenthal M. German Federal Institute for Drugs and Medical Devices. Commission E. Herbal medicine : expanded Commission E monographs. 1st. edition. Newton, MA: Integrative Medicine Communications; 2000: 519
99 Liu J, Burdette JE, Xu H, Gu C, van Breemen RB, Bhat KP, Booth N, Constantinou AI, Pezzuto JM, Fong HH, Farnsworth NR, Bolton JL. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001; 49: 2472-2479
100 Milligan SR, Kalita JC, Pocock V, Van De Kauter V, Stevens JF, Deinzer ML, Rong H, De Keukeleire D. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids. J Clin Endocrinol Metab 2000; 85: 4912-4915
101 Roelens F, Heldring N, Dhooge W, Bengtsson M, Comhaire F, Gustafsson JA, Treuter E, De Keukeleire D. Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta. J Med Chem 2006; 49: 7357-7365
102 Bovee TFH, Helsdingen RJR, Rietjens I, Keijer J, Hoogenboom R. Rapid yeast estrogen bioassays stably expressing human estrogen receptors alpha and beta, and green fluorescent protein: a comparison of different compounds with both receptor types. J Steroid Biochem Mol Biol 2004; 91: 99-109
103 Milligan S, Kalita J, Pocock V, Heyerick A, De Cooman L, Rong H, De Keukeleire D. Oestrogenic activity of the hop phyto-oestrogen, 8-prenylnaringenin. Reproduction 2002; 123: 235-242
104 Diel P, Thomae RB, Caldarelli A, Zierau O, Kolba S, Schmidt S, Schwab P, Metz P, Vollmer G. Regulation of gene expression by 8-prenylnaringenin in uterus and liver of Wistar rats. Planta Med 2004; 70: 39-44
105 Bolca S, Li J, Nikolic D, Roche N, Blondeel P, Possemiers S, De Keukeleire D, Bracke M, Heyerick A, van Breemen RB, Depypere H. Disposition of hop prenylflavonoids in human breast tissue. Mol Nutr Food Res 2010; 54: S284-S294
106 Possemiers S, Rabot S, Espin JC, Bruneau A, Philippe C, Gonzalez-Sarrias A, Heyerick A, Tomas-Barberan FA, De Keukeleire D, Verstraete W. Eubacterium limosum activates isoxanthohumol from hops (Humulus lupulus L.) into the potent phytoestrogen 8-prenylnaringenin in vitro and in rat intestine. J Nutr 2008; 138: 1310-1316
107 Bolca S, Possemiers S, Herregat A, Huybrechts I, Heyerick A, De Vriese S, Verbruggen M, Depypere H, De Keukeleire D, Bracke M, De Henauw S, Verstraete W, Van de Wiele T. Microbial and dietary factors are associated with the equol producer phenotype in healthy postmenopausal women. J Nutr 2007; 137: 2242-2246
108 Possemiers S, Bolca S, Grootaert C, Heyerick A, Decroos K, Dhooge W, De Keukeleire D, Rabot S, Verstraete W, Van de Wiele T. The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine. J Nutr 2006; 136: 1862-1867
109 Possemiers S, Heyerick A, Robbens V, De Keukeleire D, Verstraete W. Activation of proestrogens from hops (Humulus lupulus L.) by intestinal microbiota; conversion of isoxanthohumol into 8-prenylnaringenin. J Agric Food Chem 2005; 53: 6281-6288
110 Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res 2008; 22: 709-724
111 Dong S, Inoue A, Zhu Y, Tanji M, Kiyama R. Activation of rapid signaling pathways and the subsequent transcriptional regulation for the proliferation of breast cancer MCF-7 cells by the treatment with an extract of Glycyrrhiza glabra root. Food Chem Toxicol 2007; 45: 2470-2478
112 Simons R, Vincken JP, Mol LA, The SA, Bovee TF, Luijendijk TJ, Verbruggen MA, Gruppen H. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra). Anal Bioanal Chem 2011; 401: 305-313
113 Tamir S, Eizenberg M, Somjen D, Stern N, Shelach R, Kaye A, Vaya J. Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res 2000; 60: 5704-5709
114 Somjen D, Katzburg S, Vaya J, Kaye AM, Hendel D, Posner GH, Tamir S. Estrogenic activity of glabridin and glabrene from licorice roots on human osteoblasts and prepubertal rat skeletal tissues. J Steroid Biochem Mol Biol 2004; 91: 241-246
115 Somjen D, Knoll E, Vaya J, Stern N, Tamir S. Estrogen-like activity of licorice root constituents: glabridin and glabrene, in vascular tissues in vitro and in vivo . J Steroid Biochem Mol Biol 2004; 91: 147-155
116 Kang SC, Lee CM, Choi H, Lee JH, Oh JS, Kwak JH, Zee OP. Evaluation of oriental medicinal herbs for estrogenic and antiproliferative activities. Phytother Res 2006; 20: 1017-1019
117 Kim IG, Kang SC, Kim KC, Choung ES, Zee OP. Screening of estrogenic and antiestrogenic activities from medicinal plants. Environ Toxicol Pharmacol 2008; 25: 75-82
118 Hu C, Liu H, Du J, Mo B, Qi H, Wang X, Ye S, Li Z. Estrogenic activities of extracts of Chinese licorice (Glycyrrhiza uralensis) root in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 2009; 113: 209-216
119 Amato P, Christophe S, Mellon PL. Estrogenic activity of herbs commonly used as remedies for menopausal symptoms. Menopause 2002; 9: 145-150
120 Kondo K, Shiba M, Nakamura R, Morota T, Shoyama Y. Constituent properties of licorices derived from Glycyrrhiza uralensis, G. glabra, or G. inflata identified by genetic information. Biol Pharm Bull 2007; 30: 1271-1277
121 Mersereau JE, Levy N, Staub RE, Baggett S, Zogovic T, Chow S, Ricke WA, Tagliaferri M, Cohen I, Bjeldanes LF, Leitman DC. Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol 2008; 283: 49-57
122 Maggiolini M, Statti G, Vivacqua A, Gabriele S, Rago V, Loizzo M, Menichini F, Amdo S. Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem Mol Biol 2002; 82: 315-322
123 Zhang CZ, Wang SX, Zhang Y, Chen JP, Liang XM. In vitro estrogenic activities of Chinese medicinal plants traditionally used for the management of menopausal symptoms. J Ethnopharmacol 2005; 98: 295-300
124 Usui T, Ikeda Y, Tagami T, Matsuda K, Moriyama K, Yamada K, Kuzuya H, Kohno S, Shimatsu A. The phytochemical lindleyin, isolated from Rhei rhizoma, mediates hormonal effects through estrogen receptors. J Endocrinol 2002; 175: 289-296
125 Wober J, Moller F, Richter T, Unger C, Weigt C, Jandausch A, Zierau O, Rettenberger R, Kaszkin-Bettag M, Vollmer G. Activation of estrogen receptor-beta by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds. J Steroid Biochem Mol Biol 2007; 107: 191-201
126 Moller F, Zierau O, Jandausch A, Rettenberger R, Kaszkin-Bettag M, Vollmer G. Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds in U2OS human osteosarcoma cells. Phytomedicine 2007; 14: 716-726
127 Papke A, Kretzschmar G, Zierau O, Kaszkin-Bettag M, Vollmer G. Effects of the special extract ERr 731 from Rheum rhaponticum on estrogen-regulated targets in the uterotrophy model of ovariectomized rats. J Steroid Biochem Mol Biol 2009; 117: 176-184
128 Keiler AM, Papke A, Kretzschmar G, Zierau O, Vollmer G. Long-term effects of the rhapontic rhubarb extract ERr 731(R) on estrogen-regulated targets in the uterus and on the bone in ovariectomized rats. J Steroid Biochem Mol Biol 2012; 128: 62-68
129 Vollmer G, Papke A, Zierau O. Treatment of menopausal symptoms by an extract from the roots of rhapontic rhubarb: the role of estrogen receptors. Chin Med 2010; 5: 7-10
130 Park MK, Kwon HY, Ahn WS, Bae S, Rhyu MR, Lee Y. Estrogen activities and the cellular effects of natural progesterone from wild yam extract in mcf-7 human breast cancer cells. Am J Chin Med 2009; 37: 159-167
131 Cheng WY, Kuo YH, Huang CJ. Isolation and identification of novel estrogenic compounds in yam tuber (Dioscorea alata Cv. Tainung No. 2). J Agric Food Chem 2007; 55: 7350-7358
132 Wu WH, Liu LY, Chung CJ, Jou HJ, Wang TA. Estrogenic effect of yam ingestion in healthy postmenopausal women. J Am Coll Nutr 2005; 24: 235-243
133 Mirkin G. Estrogen in yams. JAMA 1991; 265: 912
134 Aradhana. Rao AR, Kale RK. Diosgenin – a growth stimulator of mammary gland of ovariectomized mouse. Indian J Exp Biol 1992; 30: 367-370
135 Liu J, Burdette JE, Sun Y, Deng S, Schlecht SM, Zheng W, Nikolic D, Mahady G, van Breemen RB, Fong HH, Pezzuto JM, Bolton JL, Farnsworth NR. Isolation of linoleic acid as an estrogenic compound from the fruits of Vitex agnus-castus L. (chaste-berry). Phytomedicine 2004; 11: 18-23
136 Ibrahim NA, Shalaby AS, Farag RS, Elbaroty GS, Nofal SM, Hassan EM. Gynecological efficacy and chemical investigation of Vitex agnus-castus L. fruits growing in Egypt. Nat Prod Res 2008; 22: 537-546
137 Jarry H, Spengler B, Porzel A, Schmidt J, Wuttke W, Christoffel V. Evidence for estrogen receptor beta-selective activity of Vitex agnus-castus and isolated flavones. Planta Med 2003; 69: 945-947
138 Choi SY, Ha TY, Ahn JY, Kim SR, Kang KS, Hwang IK, Kim S. Estrogenic activities of isoflavones and flavones and their structure-activity relationships. Planta Med 2008; 74: 25-32
139 Jarry H, Spengler B, Wuttke W, Christoffel V. In vitro assays for bioactivity-guided isolation of endocrine active compounds in Vitex agnus-castus . Maturitas 2006; 55: S26-S36
140 Hu Y, Zhang QY, Hou TT, Xin HL, Zheng HC, Rahman K, Qin LP. Estrogen-like activities in Vitex species from China determined by a cell based proliferation assay. Pharmazie 2007; 62: 872-875
141 Hu Y, Hou TT, Xin HL, Zhang QY, Zheng HC, Rahman K, Qin LP. Estrogen-like activity of volatile components from Vitex rotundifolia L. Indian J Med Res 2007; 126: 68-72
142 Hu Y, Hou TT, Zhang QY, Xin HL, Zheng HC, Rahman K, Qin LP. Evaluation of the estrogenic activity of the constituents in the fruits of Vitex rotundifolia L. for the potential treatment of premenstrual syndrome. J Pharm Pharmacol 2007; 59: 1307-1312
143 Piersen CE. Phytoestrogens in botanical dietary supplements: implications for cancer. Integr Cancer Ther 2003; 2: 120-138
144 Circosta C, Pasquale RD, Palumbo DR, Samperi S, Occhiuto F. Estrogenic activity of standardized extract of Angelica sinensis . Phytother Res 2006; 20: 665-669
145 Zhan JY, Zheng KY, Zhu KY, Bi CW, Zhang WL, Du CY, Fu Q, Dong TT, Choi RC, Tsim KW, Lau DT. Chemical and biological assessment of Angelicae Sinensis Radix after processing with wine: an orthogonal array design to reveal the optimized conditions. J Agric Food Chem 2011; 59: 6091-6098
146 Lau CB, Ho TC, Chan TW, Kim SC. Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: is it appropriate?. Menopause 2005; 12: 734-740
147 Rosenberg Zand RS, Jenkins DJ, Diamandis EP. Effects of natural products and nutraceuticals on steroid hormone-regulated gene expression. Clin Chim Acta 2001; 312: 213-219
148 Godecke T, Yao P, Napolitano JG, Nikolic D, Dietz BM, Bolton JL, van Breemen RB, Farnsworth NR, Chen SN, Lankin DC, Pauli GF. Integrated standardization concept for Angelica botanicals using quantitative NMR. Fitoterapia 2012; 83: 18-32
149 Schinkovitz A, Dietz B, Deng S, Chen SN, Pro S, Lankin D, Nikolic D, van Breemen RB, Bolton JL, Farnsworth NR, Pauli GF. The stability of Z-ligustilide and its relevance for the biological evaluation of Angelica botanicals. Planta Med 2007; 73: 817
150 Mahady GB. Is black cohosh estrogenic?. Nutr Rev 2003; 61: 183-186
151 Bodinet C, Freudenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. Breast Cancer Res Treat 2002; 76: 1-10
152 Freudenstein J, Dasenbrock C, Nisslein T. Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic Cimicifuga racemosa extract. Cancer Res 2002; 62: 3448-3452
153 Gaube F, Wolfl S, Pusch L, Kroll TC, Hamburger M. Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7. BMC Pharmacol 2007; 7: 11
154 Lupu R, Mehmi I, Atlas E, Tsai MS, Pisha E, Oketch-Rabah HA, Nuntanakorn P, Kennelly EJ, Kronenberg F. Black cohosh, a menopausal remedy, does not have estrogenic activity and does not promote breast cancer cell growth. Int J Oncol 2003; 23: 1407-1412
155 Zierau O, Bodinet C, Kolba S, Wulf M, Vollmer G. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002; 80: 125-130
156 Burdette JE, Liu J, Chen SN, Fabricant DS, Piersen CE, Barker EL, Pezzuto JM, Mesecar A, Van Breemen RB, Farnsworth NR, Bolton JL. Black cohosh acts as a mixed competitive ligand and partial agonist of the serotonin receptor. J Agric Food Chem 2003; 51: 5661-5670
157 Mercado-Feliciano M, Cora MC, Witt KL, Granville CA, Hejtmancik MR, Fomby L, Knostman KA, Ryan MJ, Newbold R, Smith C, Foster PM, Vallant MK, Stout MD. An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents. Toxicol Appl Pharmacol 2012; 263: 138-147
158 Seidlova-Wuttke D, Jarry H, Wuttke W. Effects of estradiol benzoate, raloxifen and an ethanolic extract of Cimicifuga racemosa in nonclassical estrogen regulated organs of ovariectomized rats. Planta Med 2009; 75: 1279-1285
159 Ruhlen RL, Haubner J, Tracy JK, Zhu W, Ehya H, Lamberson WR, Rottinghaus GE, Sauter ER. Black cohosh does not exert an estrogenic effect on the breast. Nutr Cancer 2007; 59: 269-277
160 Liu Z, Yang Z, Zhu M, Huo J. Estrogenicity of black cohosh (Cimicifuga racemosa) and its effect on estrogen receptor level in human breast cancer MCF-7 cells. Wei Sheng Yan Jiu 2001; 30: 77-80
161 Bolle P, Mastrangelo S, Perrone F, Evandri MG. Estrogen-like effect of a Cimicifuga racemosa extract sub-fraction as assessed by in vivo, ex vivo and in vitro assays. J Steroid Biochem Mol Biol 2007; 107: 262-269
162 Kanadys WM, Leszczynska-Gorzelak B, Oleszczuk J. Efficacy and safety of Black cohosh (Actaea/Cimicifuga racemosa) in the treatment of vasomotor symptoms – review of clinical trials. Ginekol Pol 2008; 79: 287-296
163 Benghuzzi H, Tucci M, Eckie R, Hughes J. The effects of sustained delivery of diosgenin on the adrenal gland of female rats. Biomed Sci Instrum 2003; 39: 335-340
164 Tucci M, Benghuzzi H. Structural changes in the kidney associated with ovariectomy and diosgenin replacement therapy in adult female rats. Biomed Sci Instrum 2003; 39: 341-346
165 Lu A, Beehner JC, Czekala NM, Koenig A, Larney E, Borries C. Phytochemicals and reproductive function in wild female Phayreʼs leaf monkeys (Trachypithecus phayrei crepusculus). Horm Behav 2011; 59: 28-36
166 Emery Thompson M, Wilson ML, Gobbo G, Muller MN, Pusey AE. Hyperprogesteronemia in response to Vitex fischeri consumption in wild chimpanzees (Pan troglodytes schweinfurthii). Am J Primatol 2008; 70: 1064-1071
167 Hall E, Frey BN, Soares CN. Non-hormonal treatment strategies for vasomotor symptoms: a critical review. Drugs 2011; 71: 287-304
168 Nadaoka I, Yasue M, Sami M, Kitagawa Y. Oral administration of Cimicifuga racemosa extract affects immobilization stress-induced changes in murine cerebral monoamine metabolism. Biomed Res 2012; 33: 133-137
169 Geller SE, Shulman LP, van Breemen RB, Banuvar S, Zhou Y, Epstein G, Hedayat S, Nikolic D, Krause EC, Piersen CE, Bolton JL, Pauli GF, Farnsworth NR. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 2009; 16: 1156-1166
170 Shams T, Setia MS, Hemmings R, McCusker J, Sewitch M, Ciampi A. Efficacy of black cohosh-containing preparations on menopausal symptoms: a meta-analysis. Altern Ther Health Med 2010; 16: 36-44
171 Toyohira Y, Ueno S, Tsutsui M, Itoh H, Sakai N, Saito N, Takahashi K, Yanagihara N. Stimulatory effects of the soy phytoestrogen genistein on noradrenaline transporter and serotonin transporter activity. Mol Nutr Food Res 2010; 54: 516-524
172 Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W. Interaction of various Piper methysticum cultivars with CNS receptors in vitro . Planta Med 2001; 67: 306-311
173 Ofir R, Tamir S, Khatib S, Vaya J. Inhibition of serotonin re-uptake by licorice constituents. J Mol Neurosci 2003; 20: 135-140
174 Deng S, Chen SN, Yao P, Nikolic D, van Breemen RB, Bolton JL, Fong HH, Farnsworth NR, Pauli GF. Serotonergic activity-guided phytochemical investigation of the roots of Angelica sinensis . J Nat Prod 2006; 69: 536-541
175 Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev 2012;
176 Ross SM. Menopause: a standardized isopropanolic black cohosh extract (remifemin) is found to be safe and effective for menopausal symptoms. Holist Nurs Pract 2012; 26: 58-61
177 Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Maturitas 2010; 67: 262-269
178 Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause 2010; 17: 660-666
179 Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med 2011; 171: 1363-1369
180 Wulf H. The role of soy isoflavones in menopausal health: report of The North American Menopause Society. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause 2011; 18: 732-753
181 van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002; 42: 187-193
182 Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JAMA 2003; 290: 207-214
183 Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril 2003; 79: 1112-1117
184 Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000; 7: 236-242
185 Pfitscher A, Reiter E, Jungbauer A. Receptor binding and transactivation activities of red clover isoflavones and their metabolites. J Steroid Biochem Mol Biol 2008; 112: 87-94
186 Han DH, Denison MS, Tachibana H, Yamada K. Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci Biotechnol Biochem 2002; 66: 1479-1487
187 Cheng W, Chen L, Yang S, Han J, Zhai D, Ni J, Yu C, Cai Z. Puerarin suppresses proliferation of endometriotic stromal cells partly via the MAPK signaling pathway induced by 17 ss-estradiol-BSA. PLoS One 2012; 7: e45529
188 Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 1999; 84: 2249-2252
189 Kupfer R, Swanson L, Chow S, Staub RE, Zhang YL, Cohen I, Christians U. Oxidative in vitro metabolism of liquiritigenin, a bioactive compound isolated from the Chinese herbal selective estrogen beta-receptor agonist MF101. Drug Metab Dispos 2008; 36: 2261-2269
190 Tamir S, Eizenberg M, Somjen D, Izrael S, Vaya J. Estrogen-like activity of glabrene and other constituents isolated from licorice root. J Steroid Biochem Mol Biol 2001; 78: 291-298