Phytoestrogens

Synonym(s): daidzein, genistein, isoflavonoids, lignans, red clover, soy, Tifolium pratense

Nutrient group: plant extracts & active ingredients, Hormones & hormone-like substances

Sources and physiological effects

Dietary sources
Phytoestrogens are plant substances with estrogen mimetic effects. The main representatives are lignans and isoflavones from soy and red clover. In European regions, lignans make up the majority of phytoestrogens supplied through food. Linseed is particularly rich in this phytoestrogen, but other cereals such as wheat, barley and oats also supply lignans. Vegetables also contain smaller amounts of lignans and contribute to the supply. Soya beans and products made from them (e.g. tofu, tempeh, miso) have also gained in importance as source of phytoestrogens in recent decades. Only small amounts of isoflavonoids are lost through the processing of the soybeans. Fermentation processes, such as those carried out with miso paste or certain types of tofu, increase the bioavailability of isoflavonoids. Cow's milk also contains the isoflavonoid “Equol“.
Physiological effects
Hormone	Interaction with estrogen receptors causes estrogen-like effects.
Antioxidant	Isoflavonoids and lignans have antioxidant properties.

Detailed information

Phytoestrogens: lignans and isoflavonoids

Isoflavones are primarly contained in plant pigments of yellow plants. These secondary plant substances serve the plant as a defense against pathogens. Isoflavones, also called isoflavonoids, are found in red clover and soybeans. The most important isoflavones are genistein, daidzein, glycytein and other biochemical forms.
The most important representatives of lignans are secoisolariciresinol and matairesinol, which are converted in the intestinal flora into the bioavailable enterolignans enterodiol and enterolactone (1) (2). Enterodiol can also be oxidized to enterolactone, which is the phytoestrogen with the highest serum concentration (3). The bioavailability of lignans depends not only on the amount consumed and the duration of absorption but also on individual factors, sometimes the intestinal flora. An intact intestinal flora promotes metabolism and uptake, while smoking, a high fat diet, a high BMI or a short intestinal transit time has a negative effect on enterolactone levels (2) (4). Enterolignans are excreted via bile and urine (3).

Estrogen mimetic properties of phytoestrogens

In contrast to synthetic estrogens, which have the same effect as the body's own estrogen, phytoestrogens show estrogen-mimetic properties. They are not identical in construction but can bind to the same receptors as steroidal estrogens (SERM/selective estrogen receptor modulators). However, phytohormones are much less effective than the body's own estrogens (0.1%).Therefore, depending on the estrogen concentration in the blood, they can therefore weaken (antagonistic effect) or increase (agonistic effect) the effect of estrogen in the body. If there is a high estrogen level in the blood, phytohormones block the receptors for the body's own estrogen, but have a much weaker effect. If the concentration is low, the phytohormones bind to the free receptors and act weakly, but overall the effect is higher than with an unoccupied receptor (5).

Phytoestrogens for women's health

The agonistic or antagonistic effect of phytohormones makes them suitable for a wide range of indications in women.
Pre-menopause, phytohormones can reduce the risk of breast cancer and other hormone-related tumors in women with elevated estrogen levels due to their attenuating effect (6). Thus, an increased intake of isoflavonoids in the fertile phase of a woman´s life results in a reduced effect of endogenous estrogens (antiestrogenic effects), extending the cycle by 3-4 days. While an estrogenic effect can be observed in the menopause phase where there is a low endogenous estrogen concentration (7). In menopause, phytoestrogens are used as plant-source of selective estrogen receptor modulators due to their estrogen mimetic effects that do not alter FSH, LH, estradiol and progesterone (proestrogenic effects) (7). They bind mainly to the ER-beta receptor, which is found predominantly in the brain, bones, bladder and vascular epithelia, i.e. in organs that also respond to hormone replacement therapy (7).
In postmenopause, where the body's own estrogen decreases considerably, phytohormones act as a weak estrogen substitute, which helps against physical changes and reduces the risk of osteoporosis and heart attack (8) (9). In perimenopause, which can be characterized by strong fluctuations in estrogen levels, phytohormones have an inhibitory or supportive effect, i.e. they are generally balancing. This helps alleviate the typical symptoms of menopause. Phytoestrogens also have strong antioxidant and anticarcinogenic effects. They inhibit the development of cancer cells and can slow down the formation of blood vessels in tumors. Thus, phytoestrogens as secondary plant substances can also play an important health-promoting role in men. (10)

Phytoestrogens for symptoms of menopause

The positive effects of phytohormones from soy and red clover have been well studied and documented in the treatment of sysmtoms of menopause. Although the study results often differ greatly, high-quality studies in Western women show a significant effect of isoflavones compared to placebo. This suggests value in the use of phytoestrogens for menopausal complaints. The significance of the effect depends on both the dosage and the original number of hot flushes (7).
A British meta-analysis critically examining the results of red clover (Trifolium-pratense) supplementation concluded that the frequency of hot flushes in menopausal women can indeed be significantly reduced (11).
A clinical study by the University of Messina, Italy, with 389 women over 12 months confirmed the effect of genistein, the most important isoflavone from red clover and soy, on vasomotor processes during menopause. The effects were already measurable from the first month of treatment. After 12 months, the number of hot flushes in the genistein group (54 mg/d) had decreased by 56% compared to the control group. There were no changes in the endometrium (12).
Lignans also seem to have a positive influence on cognitive performance (14).

Phytoestrogens and their influence on the skin

Estrogens have a profound influence on the biological processes in the skin. Although the exact mechanisms for the correlations have not yet been scientifically clarified, there is no doubt about the role of these steroids in processes of skin aging. The decrease in thickness, collagen structures and moisture content of the skin during peri- and postmenopause clearly indicates a correlation between the estrogen content in the body and the aging processes in the skin (15).
Conversely, hormone replacement therapy (HRT) shows a structural and optical improvement of the skin parameters. The elastin content, sebum production and water binding capacity are positively influenced. In addition, blood circulation and the ability to repair micro-injuries are increased (16). Supplementation with phytoestrogens (40 mg/d) can also significantly improve the skin's appearance in terms of wrinkling and elasticity (17). At the same time, phytoestrogens inhibit the damaging activities of free radicals through their antioxidant properties (18).
Clinical studies with genistein have shown a significant reduction of photo-aging processes in skin tissue and increased protection against UV-induced carcinogenic events (19).

Phytoestrogens can improve bone density

Post-menopause, the loss of bone mass is increased by the decrease in estrogen release. The risk of osteopenia and osteoporosis is therefore significantly increased for older women. Regular supplementation with phytoestrogens from red clover and/or soy (ideally in combination with calcium and vitamin D) can reduce menopausal bone resorption within 6 months (20) and achieve positive overall results in bone density after 24 months. This is accompanied by a measurable increase in bone-specific basic phosphatases and insulin-like growth factor-1 (21). Overall, however, the studies on improving bone density and bone mineral content by phytoestrogens still show mixed results. This can be traced back to the fact that the human ability to form the more biologically active equol from isoflavonoids seems to differ individually (equol-producer phenotype) (22). In women whose intestinal flora can convert isoflavonoids to equol, bone density is 6% higher than in non-equol producers (23). The isoflavonoid daidzein ingested with food is converted into equol 7-hydroxy-3-(4'-hydroxyphenyl)chroman in the intestine by the activity of intestinal bacteria. This biochemical form has an extremely strong estrogen mimetic effect as it can bind to both ER-alpha and ER-beta receptors. Studies indicate that not all women have a microbial colonization of the intestine that is capable of this transformation (24). This could explain the unclear data on the effectiveness of isoflavonoids in different experimental groups (25). Some scientists suspect that only a third to half of the population has intestinal flora that enables the metabolism of daidzein to equol (26).

Reduction of cardiovascular risk in menopause

Regular supplementation of isoflavonoids from red clover and/or soya may reduce the increased risk of cardiovascular events during menopause (27). Isoflavonoids are effective antioxidants in both hydrophilic and lipophilic systems. In addition to protection against UV radiation, the ability of isoflavonoids to ward off lipid oxidation is of particular importance. Thus, phytoestrogens can protect the LDL cholesterol from oxidation to tissue toxic ox-LDL (18). In addition, genistein and daidzein are able to positively influence the reaction of endothelial cells to stressors such as homocysteine or ox-LDL (28). New clinical studies show an activation of epithelial NO synthase and the production of tissue-active NO by genistein as a possible mechanism for the vascular regulating effects (29).

Lignans for cancer prevention

The protective effect of enterolactone on various cancer, such as ovarian, endometrial (30) and thyroid carcinomas, is now well documented. In particular, their protective effect with regard to breast cancer has been well studied (31) (32). Clinical studies show, for example, a 16% reduction in the risk of breast cancer at high exposure to enterolignans and high enterolactone serum levels correlate with a significantly lower mortality risk in postmenopausal breast cancer patients. The protective effect of phytoestrogens on these cancers is probably due to lower endogenous estrogen levels in postmenopausal women (33).
High enterolactone also has cardioprotecitve effects, A 65% decrease in the incidence of coronary artery disease has been demonstrated (1)(34).

Reference values

Parameter	Substrate	Lab GANZIMMUN	Reference values
Estradiol	Saliva	Neuroendocrine profile test set	follicular phase: 0.2 - 10.4 pg/ml ovulation phase: 5.8 - 21.2 pg/ml luteal phase: 0.8 - 10.8 pg/ml postmenopause: < 3.2 pg/ml
Testosterone	Saliva	Neuroendocrine Profile Test Set	5.0 - 49 pg/ml
Progesterone	Saliva	Neuroendocrine profile test set	Follicular phase: 50 -100 pg/ml Ovulation phase: 100 - 150 pg/ml Luteal phase: 100 - 450 pg/ml Postmenopause: 10 - 50 pg/ml
Oestradiol/ Progesteronratio		DHEA	Saliva	Neuroendocrine Profile Test Set	90 - 460 pg/ml
Oestradiol	Serum		Follicular phase: 19.5 - 144.2 pg/ml Ovulation phase: 63.9 - 356.7 pg/ml Luteal phase: 55.8 - 214.2 pg/ml Postmenopause: < 32.2 pg/ml
Progesterone	Serum		follicular phase: 0.33 - 1.20 ng/ml luteal phase: 0.72 - 17.80 ng/ml Postmenopause: <1.00 ng/ml
Testosterone	Serum		0.14 - 0.76 ng/ml
DHEA-S	Serum		Age-specific
DHEA	Urine		< 1.2 mg/24 h

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	Treatment menopausal complaints like hot flushes, sleep disorders, mood swings	50 – 200 mg isoflavonoids/d or 2 – 5 mg genistein/d
	Preventive and concomitant therapeutic for menopausal osteoporosis	50 – 200 mg isoflavonoids/d or 2 – 5 mg genistein/d d
	For Prevention of ccardiovascular disease and arteriosclerosis	50 – 200 mg isoflavonoids/d or 2 – 5 mg genistein/d
	For the preventive of hormone-induced tumors	Isoflavonoids/d or 2 – 5 mg genistein/d

Administration

General mode of administration
When	Isoflavonoids and lignans should be taken with meals.
	Notes: Isoflavonoids and lignans should be used regularly and over a longer period of time.
Side effects
In some cases, headaches, muscle aches and nausea may occur at high doses.
Contraindications
Pregnancy and lactation Should not be used in patients with estrogen-dependent breast tumors in the past or endometrial carcinoma due to the estrogen-mimetic effect.

Interactions

Drug interactions
None	No relevant interactions are known to date.
Nutrient interactions
Minerals	The phytic acid contained in soy can reduce the absorption of calcium.

References

1) Rietjens, I. M. et al. 2016. The potential health effects of dietary phytoestrogens. British Journal of Pharmacology.
2) Clavel, T. et al. 2016. Bioavailability of lignans in human subjects. Nutrition Research Reviews. 19: 187–196.
3) Peterson, J. et al. 2010. Dietary lignans: physiology and potential for cardiovascular disease risk reduction. Nutr Rev. 68(10):571-603.
4) Aehle, E. et al. 2011. Lignans as food constituents with estrogen and antiestrogen activity. mistry. 72(18):2396-405.
5) Hahn, A. et al. 2005. Ernährung. Physiologische Grundlagen, Prävention, Therapie. 2005.
6) Birt, D. F. et al. 2001. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 90(2-3):157-77.
7) Reinhard-Hennch, B. et al. 2006. Alternative Therapiemöglichkeiten im Klimakterium. Gynäkol Geburtshilfliche Rundsch. 45:197-213.
8) Carkson, T. B., Anthony, M. S. 1998. Phytoestrogens and coronary heart disease. Baillieres Clin Endocrinol Metab. 12(4):589-604.
9) Harkness, L. S. et al. 2004. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Kealth. 13(9):1000 -7
10) Watzl, B., Leitzmann, C. Bioaktive Substanzen in Lebensmitteln. 1999.
11) Coon, J. T. et al. 2007. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine. 14(2-3):153-9.
12) D’Anna, R. et al: Effects of the phytoestrogen genistein on hot flushes; endometrium, and vaginal epithelium in post menopausal women. 2007. A 1-year randomized, double- blind, placebo-controlled study. Menopause. 14(4):648-655.
13) Cheng, G. et al. 2007. Isoflavone treatment for acute menopausal symptoms. Menopause. 14(3):468-73.
14) Kreijkamp-Kapsers, S. et al. 2007. Dietary phytoestrogen intake and cognitive function in older women. J gerontol A Biol Sci Med Sci. 62(5):556-62.
15) Verdier-Sevrain, B. et al. 2006. Biology of estrogens in skin: implications for skin aging. Exp Dermatol. 15(2):83-94.
16) Brincat, M. P. et al. Estrogens and the skin. Climacteric 2005;8(2):110-23.
17) Izumi, T. et al. 2007. Oral intake of soy isoflavone aglycone improves aged skin of adult women. J Nutr Sci Vitaminol. 53(1):57-62.
18) Watzl, B., Leitzmann, C. Bioaktive Substanzen in Lebensmitteln. 2005.
19) Wei, H. et al. 2003. Isoflavone genistein: photoprotection and clinical implications in dermatology. J Nutr. 133(11 Suppl):3811S-9S).
20) Harkness, L. S. et al. 2004. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health. 13(9):1000-7.
21) Marini, H. et al. 2007. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 146(12):839-47.
22) Wu, J. et al. 2007. Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial. Menopause. 14(5):866-74.
23) Abdi, F. et al. 2016. Effects of phytoestrogens on bone mineral density during the menopause transition: A systematic review of randomized, controlled trials. Climacteric. 19(6), 535-545.
24) Rafii, F. et al. 2003. Variations in metabolism of the soy isoflavonoid daidzein by human intestinal microfloras from different individuals. Arch Microbiol. 180(1):11-6.
25) Yuan, J. P. et al. 2007. Metabolism of dietary soy isoflavones to equol by human intestinal microflora—implications for health. Mol Nutr Food Res. 51(7):765-8.
26) Setchell, K. D. et al. 2002. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr. 132(12):3577-84.
27) Atteritano, M. et al. 2007. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 92(8):3068-75.
28) Wenzel, U. et al. 2008. Protective effects of soy-isoflavones in cardiovascular disease. Identification of molecular targets. Hamostaseologie. 28(1):85-88.
29) Si, H., Liu, D. 2007. Phytochemical genistein in the regulation of vascular function: new insights. Curr Med Chem. 14(24):2581-9.
30) Horn-Ross. et al. 2003. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst. 95(15):1158-64.
31) Buck, K. et al. 2003. Meta-analyses of lignans and enterolignans in relation to breast cancer risk. Am J Clin Nutr. 92(1):141-53.
32) Zaineddin, A. K. et al. 2011. Serum enterolactone and postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status. Int J Cancer.
33) Buck, K. et al. 2011. Serum enterolactone and prognosis of postmenopausal breast cancer. J Clin Oncol. 29(28):3730-8.
34) GanzImmun: Phyto-Östrogene – Enterolacton und Enterodiol zur Prävention von Tumor- und Herz-Kreislauf-Erkrankungen. GANZIMMUN Fachbroschüre 069. Stand 2011.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.