Mathias Schmidt1
(1)
International Society for Phyto-Sciences, Wartbergweg 15, Mattsies, 86874, Germany
Mathias Schmidt
Email: schmidt@herbresearch.de
Recently published meta-analyses clearly document the benefits of intake of isoflavones for women in menopause: isoflavones reduce the frequency and severity of hot flashes and have protective effects with respect to the development of hormone-related cancers.
Plant-based medicinal products rank highly in the field of gynaecology. Table 21.1 offers examples of well-tested medicinal plants with applications in a range of areas. This also extends to such symptoms of menopause as hot flashes; particularly significant in this respect are black cohosh, soya and red clover. Given their long-conjectured oestrogen-like effects, these plants have been referred to as ‘phytoestrogens’ in the past and have been used to treat symptoms of menopause – a classification that leads to misunderstandings.
Table 21.1
Well-tested areas of application of medicinal plant preparations
|
Sleep disorders |
Valerian (Valeriana officinalis), lemon balm (Melissa officinalis) |
|
Nervous agitation |
Purple passion flower (Passiflora incarnata) |
|
Depressed mood |
Common St John’s wort (Hypericum perforatum) |
|
Urinary tract infections |
Cranberry (Vaccinium marcrocarpon) |
|
Irritable bladder |
Pumpkin (Cucurbita pepo) |
|
Hepatic disease |
Mary Thistle (Silybum marianum) |
|
Dyspepsia, bile flow |
Artichoke (Cynara scolymus) |
|
Pain, fever |
White willow bark (Salix alba) |
|
Inflammation, rheumatism |
Devil’s claw (Harpagophytum procumbens) |
|
Blunt injuries |
Common comfrey (Symphytum officinale) |
|
Premenstrual syndrome |
Chaste tree (Vitex agnus-castus) |
|
Menopausal symptoms |
Black cohosh (Cimicifuga racemosa), soybean (Glycine max), red clover (Trifolium pratense) |
21.1 ‘Phytoestrogens’? A Misleading Term
The idea that plants could have effects ‘like oestrogen’ ultimately dates back to observations anomalies in the menstrual cycles of hop pickers. The common hop (Humulus lupulus) contains the ingredient 8-Prenylnaringenin, a flavonoid of which very large quantities can in fact activate the oestrogen alpha receptor, triggering hormonal effects in the process. These effects may be difficult to achieve with the usual amounts of hop extracts (those found in plant-based sedatives, for instance).
In 1946, when fertility problems were observed in sheep in Australia, based on experience with hops, the effect was quickly attributed to a plant that is used to treat the symptoms of menopause: the red clover (Trifolium pratense) found growing in the meadows where the sheep were grazing [1]. The discrepancy that European livestock also graze on red clover, yet that the plant fails to trigger any fertility problems here, was never discussed and should have prompted massive doubts about the attribution of blame to red clover. Red clover contains isoflavones, isoflavones help alleviate menopausal symptoms; ergo and isoflavones have contraceptive endocrine effects. This is how a plant that is otherwise in good standing can slide into disrepute. In point of fact, the effects of isoflavones are manifested not via the oestrogen alpha receptor; instead, they activate the oestrogen beta receptor.
In contrast to soya and red clover, other plant extracts used in menopause exhibit other mechanisms: black cohosh (Cimicifuga racemosa) does not work through oestrogen receptors at all; rhapontic rhubarb (Rheum rhaponticum), on the other hand, with the ingredient rhaponticin, contains stilbestrols, which in turn activate the oestrogen alpha receptor. The term ‘phytoestrogen’ would be more fitting in the case of rhubarb but not for the isoflavones found in red clover or soya. A more apt designation here would be that of ‘selective oestrogen receptor modulators’ (phytoSERMs).
21.2 The Oestrogen Beta Receptor Protects Against Excessive Hormonal Effects
Classic oestrogen effects such as the proliferation of breast and uterine tissue are controlled via the oestrogen alpha receptor. The oestrogen beta receptor is activated by oestrogen as well. The effects that this produces protect against excessive activation of the alpha receptor, for instance, during cycle phases involving high oestrogen levels. The oestrogen beta receptor was only discovered in 1996 [2], and soon thereafter, it was found that isoflavones can activate this protective receptor type [3]. The oestrogen beta receptor is expressed primarily in hormone-sensitive tissues, such as the breast and the uterus, and also in the bones and in the cardiovascular system.
21.3 The Significance of 3β Adiol in Menopause
Estradiol is not the only physiological binding partners on the ER-β. The research findings of recent years point to a complex pattern of activation and modulation of the oestrogen receptors not only by oestrogen itself but also by a metabolite of androgens: 5α-androstan-3β, 17β-diol, also known as ‘3β adiol’. This metabolite no longer has any androgenic effects, but it does not trigger any oestrogenic effects on ER-α or -3β adiol [4], a specific ER-β agonist with a contribution to hormonal balance in the female organism.
In fact, 3β adiol is formed in the female organism even before the emergence of significant quantities of oestrogen in puberty. During the fertile years, blood levels of 3β adiol parallel those of oestrogen [5, 6]. This parallel development could contribute to an understanding of why, despite the proliferation-promoting effects of oestrogen at ER-α, the regular occurrence of very high levels of oestrogen in puberty and during the menstrual cycle and pregnancy does not lead to an increased incidence of cancer. During menopause, on the other hand, levels of both hormones, oestrogen and 3β adiol, are reduced [7, 8].
21.3.1 Protective Effect of Isoflavones
Thus, the onset of menopausal symptoms correlates not only with reduced levels of oestrogen but also with reduced 3β adiol levels [9] – and hence with a reduced activation of ER-β (Fig. 21.1).
Fig. 21.1
Structures of estradiol and 3β adiol and of the isoflavones genistein and daidzein
Activation of ER-beta by high oestrogen levels, by 3β adiol, as well as by isoflavones does the following:
· Triggers protective effects against excessive proliferation of breast or uterine tissue
· Counteracts increased bone resorption due to oestrogen
· Produces protective effects in the cardiovascular system
· Reduces vasomotor complaints during menopause
The connection between soya and a reduced incidence of menopausal symptoms and also between osteoporosis and hormone-related types of cancer such as breast cancer and uterine cancer has long since been identified in epidemiological investigations, particularly in studies from Asian countries. Early on, this effect was attributed to the group of isoflavones; the typical daily intake as part of a traditional Asian diet is 30–100 mg (calculated as genistein), while a Western diet typically reaches amounts of no more than 1–2 mg per day. The quantities consumed in Asia are sufficient to activate the oestrogen beta receptor [10]; a Western diet is not expected to have this result.
21.4 Reduction of Menopausal Symptoms Demonstrated Beyond a Doubt
The reduction of menopause-related hot flashes through isoflavones has been clearly documented. In a currently published meta-analysis, ten double-blind studies were subjected to a more precise statistical review, the result of which was that there can be no doubt of the superiority of isoflavones to placebo [11]. This was quantified in further current reviews of 16 or 17 double-blind studies; in terms of the reported frequency and severity of hot flashes, isoflavones were 25–26 % more effective than placebo, and they achieved 57 % of the potency of oestrogen [12, 13]. With this in mind, the Austrian Menopause Association [Menopausegesellschaft] has thus recommended that isoflavones be used first in the treatment of menopausal symptoms before hormone replacement therapy is considered [14].
21.4.1 Isoflavones: Proven Safety in Controlled Studies
Hormone-based treatment was called into question as a result of the WHI study after it was found that the administration of hormones increased the risk of stroke and breast cancer [15]. This was subsequently corrected by identifying the increased risk as the product not of the oestrogen component but of the combination with a synthetic progestogen component [16] – and yet, for reasons that defy logic, the WHI study was used as an occasion to attribute the same kind of risk to the isoflavones derived from soya and red clover as well. Since that time, the hormonal safety of isoflavones has formed the subject of a multiplicity of studies: not only was the absence of tumour-promoting effects documented, but also isoflavones were shown to have preventive effects. The experimental investigations on animals have even taken on a curative purpose; a recent study most impressively demonstrated the decline in the size of tumours in animal breast tissue concomitant to increasing quantities of genistein [17]. This is consistent with the current development of genistein derivatives for use as angiogenesis inhibitors in cancer therapy.
The abovementioned observation made in animal experiments is consistent with the findings of clinical studies. A literature review conducted by the International Society for Phyto-Sciences found 58 studies with more than 6000 women exposed to isoflavones (44 studies of which were double-blind in design), in the course of which hormonal safety parameters were measured (Table 21.2). The study lasted up to 3 years, with daily quantities of isoflavones administered ranging between 36 and 300 mg. None of these studies found evidence of a negative effect of isoflavones on tumour growth or a tumour risk.
Table 21.2
Typical hormonal safety parameters in clinical studies with isoflavones
|
Mammography and breast tissue density |
|
Nipple aspirate fluid |
|
Endometrium biopsies |
|
Ultrasound examinations of the uterus |
|
Vaginal smears |
|
Hormone levels (E2, LH, FSH, SHBG) |
Current reviews and meta-analyses arrived at similar results; on the basis of double-blind, long-term studies, experts now acknowledge that the safety of high doses of isoflavones is beyond question [18, 19]. This finding applies to breast tissue and the endometrium alike; in one placebo-controlled study, isoflavones were administered to 224 women over 3 years in doses of 80 or 120 mg. There was no change in the thickness of the endometrium [18].
21.5 Effects of Tamoxifen Not Diminished
Isoflavones have preventive effects relative to hormone-dependent tumours, effects that benefit women already diagnosed with breast cancer [20]. Isoflavones do not disrupt treatments with tamoxifen and in fact tend to demonstrate synergistic effects [21–23], which could open up interesting therapeutic options for the future. Guha et al. (2008) examined women with isoflavone intake of the kind achieved through a diet rich in soya (an average of 47.4 mg/day in the group with the highest intake). The study found no disruptive effect whatsoever with regard to the efficacy of tamoxifen. On the contrary, the data among those with a high intake of isoflavones indicated a reduced recurrence of breast cancer.
21.6 Protective Effects of Isoflavones Epidemiologically Confirmed
Overall, the literature review conducted by the International Society for Phyto-Sciences identified at least 45 epidemiological and case-control studies of more than 500,000 women with exposure to isoflavones. In all cases, depending on the research questions involved, either cancer-preventive effects or an absence of cancer-inducing effects in the breast and endometrium was confirmed. A meta-analysis calculated a reduction in the relative risk of breast cancer of around 16 % for every 10 mg of isoflavones administered per day [24]. Long-term administration of isoflavones also improves the long-term prognosis in women with breast cancer.
21.7 Results of Asian Studies Are Transferable
In the past, the epidemiological studies were criticised for not being applicable to women with Western dietary habits. Indeed, a large part of the studies comes from Asian countries. But the issue of transferability has since been answered in the affirmative; for instance, a recently published, multiethnic cohort study described the data of 84,450 women who were observed over a period of 13 years. Once again, it was confirmed that isoflavones do not increase the risk of breast cancer and that the preventive effect correlates with the quantity of isoflavones administered [25]. A further current study from Canada described the long-term observation of 6500 women. Long-term administration of isoflavones was reflected in an average risk reduction of 32 %. The combination of high dosage with a duration of 5 years or more increased the protective effect to 45 % [26].
21.8 Summary
Isoflavones rank among the most thoroughly tested natural substances. Research over the past 10 years has focussed on a demonstration of effects and safety, particularly with regard to women in menopause. Both administration for menopausal symptoms and safety have been confirmed beyond doubt in meta-analyses and thus meet the gold standard of evidence-based medicine. Isoflavone intake statistically significantly reduces the frequency and severity of hot flashes compared to placebo. At the same time, even for long-term administration over many years and in high dosages, there is no discernible oestrogen risk – even and explicitly where the users are women with a previous history of breast cancer. Levels of tamoxifen were unaffected. Even with high levels of isoflavone intake spanning 3 years, the thickness of the endometrium remained unchanged. Accordingly, the risk-benefit balance of isoflavones must be considered clearly positive for women in menopause.
References
1.
Bennets HW, Underwood EJ, Shier FLA (1946) A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Aust Vet J 22:2–12CrossRef
2.
Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 93(12):5925–5930PubMedCentralCrossRefPubMed
3.
Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT et al (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139(10):4252–4263PubMed
4.
Pettersson H, Holmberg L, Axelson M, Norlin M (2008) CYP7B1-mediated metabolism of dehydroepiandrosterone and 5alpha-androstane-3beta,17beta-diol--potential role(s) for estrogen signaling. FEBS J 275(8):1778–1789CrossRefPubMed
5.
Remer T, Boye KR, Hartmann MF, Wudy SA (2005) Urinary markers of adrenarche: reference values in healthy subjects, aged 3–18 years. J Clin Endocrinol Metab 90(4):2015–2021CrossRefPubMed
6.
Mishra RG, Stanczyk FZ, Burry KA, Oparil S, Katzenellenbogen BS, Nealen ML et al (2006) Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity. Am J Physiol Heart Circ Physiol 290(1):H295–H303CrossRefPubMed
7.
Wright F, Mowszowicz I, Mauvais-Jarvis P (1978) Urinary 5 alpha-androstane-3 alpha,17 beta-diol radioimmunoassay: a new clinical evaluation. J Clin Endocrinol Metab 47(4):850–854CrossRefPubMed
8.
Labrie F, Belanger A, Cusan L, Gomez JL, Candas B (1997) Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 82(8):2396–2402CrossRefPubMed
9.
Barbaccia ML, Lello S, Sidiropoulou T, Cocco T, Sorge RP, Cocchiarale A et al (2000) Plasma 5alpha-androstane-3alpha,17betadiol, an endogenous steroid that positively modulates GABA(A) receptor function, and anxiety: a study in menopausal women. Psychoneuroendocrinology 25(7):659–675CrossRefPubMed
10.
Harris DM, Besselink E, Henning SM, Go VL, Heber D (2005) Phytoestrogens induce differential estrogen receptor alpha- or Beta-mediated responses in transfected breast cancer cells. Exp Biol Med 230(8):558–568
11.
Chen MN, Lin CC, Liu C (2014) Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric 29:1–21
12.
Li L, Lv Y, Xu L, Zheng Q (2014) Quantitative efficacy of Soy isoflavones on menopausal hot flashes. Br J Clin Pharmacol 15
13.
Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M (2012) Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 19(7):776–790CrossRefPubMed
14.
Anon (2007) Positionspapier der Internationalen und österreichischen Menopausegesellschaft. Sekretariat österreichische Menopausegesellschaft
15.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333CrossRefPubMed
16.
Beral V (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362(9382):419–427CrossRefPubMed
17.
Fan P, Fan S, Wang H, Mao J, Shi Y, Ibrahim MM et al (2013) Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway. Stem Cell Res & Ther 4(6):146CrossRef
18.
Alekel DL, Genschel U, Koehler KJ, Hofmann H, Van Loan MD, Beer BS et al (2014) Soy isoflavones for reducing bone loss study: effects of a 3-year trial on hormones, adverse events, and endometrial thickness in postmenopausal women. Menopause 7
19.
Quaas AM, Kono N, Mack WJ, Hodis HN, Felix JC, Paulson RJ et al (2013) Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial. Menopause 20(8):840–844PubMedCentralCrossRefPubMed
20.
Kang HB, Zhang YF, Yang JD, Lu KL (2012) Study on soy isoflavone consumption and risk of breast cancer and survival. Asian Pac J Cancer Prev 13(3):995–998CrossRefPubMed
21.
Wu AH, Pike MC, Williams LD, Spicer D, Tseng CC, Churchwell MI et al (2007) Tamoxifen, soy, and lifestyle factors in Asian American women with breast cancer. J Clin Oncol 25(21):3024–3030CrossRefPubMed
22.
Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ (2009) Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the life after cancer epidemiology study. Breast Cancer Res Treat 118(2):395–405PubMedCentralCrossRefPubMed
23.
Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W et al (2009) Soy food intake and breast cancer survival. JAMA 302(22):2437–2443PubMedCentralCrossRefPubMed
24.
Wu AH, Yu MC, Tseng CC, Stanczyk FZ, Pike MC (2009) Dietary patterns and breast cancer risk in Asian American women. Am J Clin Nutr 89(4):1145–1154CrossRefPubMed
25.
Morimoto Y, Maskarinec G, Park SY, Ettienne R, Matsuno RK, Long C et al (2014) Dietary isoflavone intake is not statistically significantly associated with breast cancer risk in the Multiethnic Cohort. Br J Nutr 112(6):976–983PubMedCentralCrossRefPubMed
26.
Boucher BA, Cotterchio M, Anderson LN, Kreiger N, Kirsh VA, Thompson LU (2013) Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk. Int J Cancer 132(6):1439–1450CrossRefPubMed