In my last post, I discussed the benefits of phytoestrogens, and how these plant compounds may help to regulate the effects of estrogen. While soy foods are perhaps the best-known phytoestrogens, there are a number of herbs with apparent phytoestrogenic properties that have a long history of use in herbal medicine. Current research has demonstrated the usefulness of these botanicals in protecting breast and prostate health.
The following herbs are among those that I use extensively in my practice:
Red clover (Trifolium pratense L.) extract
Often used as an alterative in herbal medicine, red clover historically was used to improve cellular nutrition and lymphatic drainage, and is often found in many traditional herbal formulations for cancer.
Red clover flowers were a key ingredient of a famous Eclectic medical formulation called “Trifolium Compound.” The ingredients included fresh extracts of Trifolium pratense, Stillingia sylvatica, Lappa minor, Phytolacca decandra, Cascara amarga, Berberis aquifolium, Podophyllum peltatum, Xanthoxylum carolinianum and potassium iodide. It was intended for administration “in syphilis, scrofula, chronic rheumatism, glandular and various skin affections.”1 The popularization of red clover as a cancer treatment in the first half of the last century derived from various sources, including Jethro Kloss, and the controversial Harry Hoxsey, whose anticancer “Hoxsey Formula” incorporated most of the herbs of the original Trifolium Compound, including red clover flowers. Hoxsey formula type products persist in the retail marketplace today.2
While the traditional preparation of red clover contains only trace amounts of phytoestrogens, the standardized modern version of the plant extract contains significant amounts. Red clover blossoms contain the isoflavones formononentin and biochanin A, neither of which is found in soy. These compounds are partially metabolized in vivo to the estrogenic metabolite equol, which has protective properties.
Red clover has demonstrated tumor-suppressing ability in breast and prostate cancer models through diverse mechanisms. These include the stabilization of gene behavior (PTEN, Bcl-2/Bax), inactivation of various transduction pathways (insulin-like growth factor 1(IGF1)/IGF1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway) including inflammatory pathways such as NF-kB, and the selective suppression of cancer cell angiogenesis.
A number of studies suggest that red clover extract does not induce or promote breast cancer and appears to be protective for breast tissue:
- In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, a clinical trial by Atkinson et al (2004) evaluated the effects of an isoflavone-rich red clover extract supplement on mammographic breast density in women. Effects on breast density, oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were assessed after one year of taking the extract. Researchers found the isoflavone supplement did not increase mammographic breast density. Furthermore, there were no effects on estradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.4
- The estrogenicity and ER binding properties of different isoflavone compounds in a “red clover clinical extract” were analyzed by Booth and coworkers (2006). All the isoflavones, except formononetin, showed binding activity to one or another recombinant ER type.5
- Polymorphisms between “fast” and slow” equol producers have been described; likewise, equol undergoes enterohepatic recirculation. Biochanin A and formononetin may additionally be metabolized in hepatocytes to genistein and daidzein.6,7 Furthermore, biochanin A, the principle isoflavone in red clover extract, inhibited aromatase activity and hampered breast cancer cell growth.8 Biochanin A and formononetin may also reduce and possibly reverse multi-drug resistance by inhibiting P-glycoprotein-mediated efflux, suggesting they could potentially increase the absorption/bioavailability of coadministered drugs that are P-gp substrates.
In certain in vitro settings many popular herbal supplements and even common foods such as peas, legumes, and seeds contain phytochemical components that when studied as a drug (meaning in isolation at high concentrations) are capable of binding to human estrogen receptors and exhibit selective estrogen receptor modulation.10
Black cohosh (Actaea racemosa syn. Cimicifuga racemosa) extract
Two hundred years ago, Native Americans used the root of the black cohosh plant to relieve menstrual cramps and symptoms of menopause, such as hot flashes, irritability, and insomnia. Today, black cohosh continues to be employed as one of the primary botanicals for easing the symptoms of PMS, dysmenorrhea, and menopausal discomfort.
Although some authors suggest that black cohosh root contains substances with selective estrogen receptor modulator (SERM) activity, this has never actually been demonstrated. In fact, recent data indicates that black cohosh may have an effect on dopaminergic and serotoninergic systems. Based on 26 articles (14 randomized controlled trials, 7 uncontrolled trials, and 5 observational studies) current evidence does not support an association between black cohosh and an increased risk of breast cancer.11,12
Multiple laboratory studies have investigated a possible link between black cohosh and breast cancer. When we look at a few of the more relevant studies, they indicate that black cohosh is safe when used in cases of breast cancer:
- In a prospective observational study researching black cohosh in tamoxifen-treated breast cancer patients with climacteric complaint, researchers concluded that black cohosh extract seems to be a reasonable treatment approach in tamoxifen-treated breast cancer patients with predominantly psychovegetative symptoms.13
- An in vitro study found a synergistic cytotoxic effect of tamoxifen and black cohosh on MCF-7 and MDA-MB-231 human breast cancer cells.14
- In a similar study, black cohosh displayed significant inhibition of MCF-7 cell proliferation. Moreover, the proliferation-inhibiting effect of tamoxifen was enhanced by black cohosh extract. Such data that suggest a non-estrogenic, or estrogen-antagonistic effect of black cohosh on human breast cancer cells may provide a safe, natural remedy for menopausal symptoms in breast cancer.15
- Furthermore, in the presence of estrogen, black cohosh extract antagonized estradiol-induced activities. Estradiol induced stimulation of proliferation was inhibited by a dosage >1 microg/ml of extract concentration and gene expression was suppressed by doses of 100-1000 microg/ml of black cohosh extracts. From the results of this and similar studies, researchers concluded that black cohosh extract displayed antiestrogenic properties16 and can protect against cellular DNA damage caused by reactive oxygen species by acting as redox/antioxidant.17
- Using a population-based case-control study, researchers from the University of Pennsylvania School of Medicine evaluated 949 breast cancer cases and 1,524 control cases. Demographic information and the use of hormone-related supplements were identified using questionnaires. After adjusting for potential confounding factors, the use of black cohosh was associated with a 61 per cent reduction in the risk of breast cancer. This risk reduction was also observed for black cohosh extract (Remifemin), which was calculated to reduce the risk of breast cancer by 53 per cent.18
- A further study published in March 2007 explored the use of black cohosh in18,861 breast cancer patients, of whom 1,102 had taken black cohosh. Their results showed that taking black cohosh was associated with prolonged disease-free survival. After 2 years following initial diagnosis, 14% of the control group had developed a cancer recurrence. It took 6.5 years for cohosh takers to reach this same proportion of recurrences. Comparing the two groups, the cohosh users had a rate of recurrence that was 83% less than the nonusers.19
Hops (Humulus lupulus)
The flowers (or strobiles) of the hops plant have been used for centuries for brewing beer, but they have been equally valued in herbal medicine for a variety of health issues, including anxiety, insomnia, indigestion, and improving the flow of breast milk for nursing mothers. Research indicates that hops has phytoestrogenic and anticancer properties.
Hops contain 4–14% polyphenols, mainly phenolic acids, chalcones, flavonoids, catechins, and proanthocyanidins. A number of prenylflavonoids are present in hops, among which 8-prenylnaringenin and xanthohumol are often referred to as phytoestrogens. Hops has anticarcinogenic properties via a broad spectrum of inhibitory mechanisms at the initiation, promotion, and progression stage of carcinogenesis.20
Hops extract rich in xanthohumol (XN), the major prenylflavonoid, has demonstrated both breast and prostate cancer suppressing effects.21 Mechanisms included the inhibition of NF-kB,22 blockage of hormone receptor binding,23 cytoprotective,24 inhibition of the efflux transporter breast cancer resistance protein,25 inhibition of oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells,26 and inhibition of aromatase (reducing estrogen).
Monteiro et al. (2007) studied the effect of the prenylflavonoids xanthohumol, isoxanthohumol and 8-prenylnaringenin on the breast cancer Sk-Br-3 cell line proliferation, apoptosis and activity of the enzyme aromatase. The results showed that all tested prenylflavonoids were able to inhibit aromatase activity and thus, estrogen formation. These findings add weight to the idea that hop flavonoids may have anti-breast cancer effects and shed new light on a possible mechanism of action by which these effects occur, namely through their ability to decrease estrogen synthesis.27
Licorice root (Glycyrrhiza glabra and species)
Licorice, a member of the pea family, is one of the oldest and most frequently employed botanicals in Chinese medicine. Licorice root is often used in small to moderate amounts to harmonize the characteristics of other plants, and to bring the formula together energetically—similar to using a common spice in creating a gourmet meal. The estrogenic activity of licorice is attributed to the compound isoliquiritigenin.28
Licorice also contains triterpenoids, glycyrrhizin, and glycyrrhizic acid, which displays more of an adrenal cortical conservation effect than an estrogenic effect.29 Licorice extract has demonstrated a stress protective effect from the overstimulation of cortisone affecting the thymus and adrenal gland.30
In studies, licorice extract has been shown to inhibit cancer-related inflammation (targets NF-KB, RANKL, LOX-5, COX-2, TNF-a) suppressing the growth of a number of cancers including colon,31,32 prostate,33,34 and breast in animal models.35-40 A recent study found that glycyrrhetinic acid (GA) potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. This study demonstrated that GA effectively suppresses breast tumor outgrowth and pulmonary metastasis without causing animal weight loss or eliciting liver/kidney toxicity to the recipient animals.41
As is obvious from the extensive research outlined above, phytoestrogens offer a simple, safe, and effective tool for supporting health, particularly for the hormone sensitive tissues found in the breast and prostate. The diverse ways in which these compounds act to protect and enhance health is precisely the reason that I rely on botanicals and natural foods to provide the body with what it needs for optimal wellbeing.
- Felter H, Lloyd J. Trifolium. King’s American Dispensatory. 2 vol. 1898 Reprint ed. Sandy, OR: Eclectic Medical Publications Reprint 1983; 1898:1995-1996.
- Brinker F. The Hoxsey Treatment: Cancer quackery or effective physiological adjuvant? J Naturopathic Med 1996;6:9-2
- Krenn L, Paper DH. Inhibition of angiogenesis and inflammation by an extract of red clover (Trifolium pratense L.). 2009 Dec;16(12):1083-8. Epub 2009 Aug 7.
- Atkinson C1, Warren RM, Sala E, Dowsett M, Dunning AM, Healey CS, Runswick S, Day NE, Bingham SA. Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165]. Breast Cancer Res. 2004;6(3):R170-9. Epub 2004 Feb 24.
- Booth NL, Overk CR, Yao P et al. The Chemical and Biologic Profile of a Red Clover (Trifolium pratense L.) Phase II Clinical Extract. J Altern Complement Med 2006;12:133-139
- Setchell KD. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 1998;68:1333S-1346S.
- Tolleson WH, Doerge DR, Churchwell MI et al. Metabolism of biochanin A and formononetin by human liver microsomes in vitro. J Agric Food Chem 2002;50:4783-4790.
- Wang Y, Man Gho W, Chan FL, Chen S, Leung LK. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression, Br J Nutr. 2008 Feb;99(2):303-10. Epub 2007 Aug 29.
- Zhang S, Morris ME. Effect of the flavonoids biochanin A and silymarin on the P-glycoprotein-mediated transport of digoxin and vinblastine in human intestinal Caco-2 cells. Pharm Res 2003;20:1184-1191
- Powers CN1, Setzer WN A molecular docking study of phytochemical estrogen mimics from dietary herbal supplements, In Silico Pharmacol. 2015 Mar 22;3:4. doi: 10.1186/s40203-015-0008-z. eCollection 2015
- Kanadys WM1, Leszczyńska-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 Apr;79(4):287-96.
- Fritz H, Seely D, McGowan J, Skidmore B, Fernandes R, Kennedy DA, Cooley K, Wong R, Sagar S, Balneaves LG,Fergusson D. Black Cohosh and Breast Cancer: A Systematic Review, Integr Cancer Ther. 2013 Mar 25.
- Rostock M, Fischer J, Mumm A, Stammwitz U, Saller R, Bartsch HH. Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients with climacteric complaints – a prospective observational study, Gynecol Endocrinol. 2011 Jan 13.
- Al-Akoum M1, Dodin S, Akoum A. Synergistic cytotoxic effects of tamoxifen and black cohosh on MCF-7 and MDA-MB-231 human breast cancer cells: an in vitro study, Can J Physiol Pharmacol. 2007 Nov;85(11):1153-9.
- Bodinet C, Freudenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. Breast Cancer Res Treat. 2002 Nov;76(1):1-10.
- Zierau O, Bodinet C, Kolba S, Wulf M, Vollmer G. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol. 2002 Jan;80(1):125-30.
- Burdette JE, Chen SN, Lu ZZ, Xu H, White BE, Fabricant DS, Liu J, Fong HH, Farnsworth NR, Constantinou AI, Van Breemen RB, Pezzuto JM, Bolton JL. Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA damage through scavenging of reactive oxygen species: bioassay-directed isolation and characterization of active principles. J Agric Food Chem. 2002 Nov 20;50(24):7022-8.
- Rebbeck TR, et al. A retrospective case-control study of the use of hormone-related supplements and association with breast cancer. Int J Cancer. 2007 Apr 1;120(7):1523-8.
- Zepelin HH, ete al. Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther. 2007 Mar;45(3):143-54
- 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 Aug 10;53(16):6281-8.
- Clarissa Gerhauser, Axel Alt, Elke Heiss, Amira Gamal-Eldeen, Karin Klimo, Jutta Knauft, Isabell Neumann, Hans-Rudolf Scherf, Norbert Frank, Helmut Bartsch and Hans Becker, Cancer Chemopreventive Activity of Xanthohumol, a Natural Product Derived from Hop, March 24–28, 2001 in New Orleans, LA (64). 1 — Mol Cancer Ther
- Colgate EC, Miranda CL, Stevens JF, Bray TM, Ho E. Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells. Cancer Lett. 2007 Feb 8;246(1-2):201-9. Epub 2006 Mar 24.
- Deeb D, Gao X, Jiang H, Arbab AS, Dulchavsky SA, Gautam SC. Growth inhibitory and apoptosis-inducing effects of xanthohumol, a prenylated chalone present in hops, in human prostate cancer cells., Anticancer Res. 2010 Sep;30(9):3333-9.
- Dietz BM, Hagos GK, Eskra JN, Wijewickrama GT, Anderson JR, Nikolic D, Guo J, Wright B, Chen SN, Pauli GF, van Breemen RB, Bolton JL. Differential regulation of detoxification enzymes in hepatic and mammary tissue by hops (Humulus lupulus) in vitro and in vivo. Mol Nutr Food Res. 2013 Mar 20. doi: 10.1002/mnfr.201200534
- Tan KW, Cooney J, Jensen D, Li Y, Paxton JW, Birch NP, Scheepens A. Hop-derived prenylflavonoids are substrates and inhibitors of the efflux transporter breast cancer resistance protein (BCRP/ABCG2). Mol Nutr Food Res.
- Hemachandra LP, Madhubhani P, Chandrasena R, Esala P, Chen SN, Main M, Lankin DC, Scism RA, Dietz BM, Pauli GF, Thatcher GR, Bolton JL. Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A). Cancer Prev Res (Phila). 2012 Jan;5(1):73-81. doi: 10.1158/1940-6207.CAPR-11-0348. Epub 2011 Oct 13.
- Monteiro R, Faria A, Azevedo I, Calhau C. Modulation of breast cancer cell survival by aromatase inhibiting hop (Humulus lupulus L.) flavonoids. J Steroid Biochem Mol Biol. 2007 Jun-Jul;105(1-5):124-30. Epub 2007 Jul 23.
- Hajirahimkhan A1, Simmler C, Yuan Y, Anderson JR, Chen SN, Nikolić D, Dietz BM, Pauli GF, van Breemen RB, Bolton JL. Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms, PLoS One. 2013 Jul 12;8(7):e67947. doi: 10.1371/journal.pone.0067947.
- Whorwood CB. Sheppard MC, Stewart PM. Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action.Endocrinology 1993; 132 (6): 2287-92.
- Heilmann P, Heide J, Hundertmark S, Schoneshofer M. Administration of glycyrrhetinic acid: significant correlation between serum levels and the cortisol/cortisone-ratio in serum and urine. Exp Clin Endocrinol Diabetes. 1999;107(6):370-8.
- Takahashi T, Takasuka N, Iigo M, Baba M, Nishino H, Tsuda H, Okuyama T. Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Japan. Cancer Sci. 2004 May;95(5):448-53.
- Khan R1, Khan AQ, Lateef A, Rehman MU, Tahir M, Ali F, Hamiza OO, Sultana S. Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats, PLoS One. 2013;8(2):e56020. doi: 10.1371/journal.pone.0056020. Epub 2013 Feb 14.
- Fu Y, Hsieh TC, Guo J, Kunicki J, Lee MY, Darzynkiewicz Z, Wu JM. Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochem Biophys Res Commun. 2004 Sep 10;322(1):263-70.
- Yi-Te Yo, et al. Licorice and Licochalcone-A Induce Autophagy in LNCaP Prostate Cancer Cells by Suppression of Bcl-2 Expression and the mTOR Pathway, J. Agric. Food Chem.
- Lee YM, Lim do Y, Choi HJ, Jung JI, Chung WY, Park JH. Induction of cell cycle arrest in prostate cancer cells by the dietary compound isoliquiritigenin. J Med Food. 2009 Feb;12(1):8-14.
- Kanazawa M, Satomi Y, Mizutani Y, Ukimura O, Kawauchi A, Sakai T, Baba M, Okuyama T, Nishino H, Miki T. Isoliquiritigenin inhibits the growth of prostate cancer. Eur Urol. 2003 May;43(5):580-6.
- Lee SK, Park KK, Park JH, Lim SS, Chung WY. The Inhibitory Effect of Roasted Licorice Extract on Human Metastatic Breast Cancer Cell-Induced Bone Destruction.Phytother Res. 2013 Feb 11. doi: 10.1002/ptr.4930.
- Wang Z, Wang N, Han S, Wang D, Mo S, Yu L, Huang H, Tsui K, Shen J, Chen J. Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLoS One. 2013 Jul 5;8(7):e68566. doi: 10.1371/journal.pone.0068566.
- 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 Oct 15;60(20):5704-9.
- Jo EH, Hong HD, Ahn NC, Jung JW, Yang SR, Park JS, Kim SH, Lee YS, Kang KS. Modulations of the Bcl-2/Bax family were involved in the chemopreventive effects of licorice root (Glycyrrhiza uralensis Fisch) in MCF-7 human breast cancer cell. J Agric Food Chem. 2004 Mar 24;52(6):1715-9.
- Ye L, Gho WM, Chan FL, Chen S, Leung LK. Dietary administration of the licorice flavonoid isoliquiritigenin deters the growth of MCF-7 cells overexpressing aromatase. Int J Cancer. 2009 Mar 1;124(5):1028-36.