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The use and efficacy of (dietary) phytoestrogens in menopause

Phytoestrogens are plant compounds that are structurally similar to estradiol. As they can interact with estrogen receptors (ER) and influence other signalling pathways, supplemental phytoestrogens and the plant foods they come from represent an alternative therapy to hormone-replacement treatment (HRT) in perimenopausal and menopausal women.

Estradiol plays multiple roles in the overall health of women including protection of the cardiovascular system and of bone density. Therefore its decline, associated with menopause, can increase the risk of atherosclerosis, decreased bone density and osteoporosis.

Common symptoms include vaginal dryness and atrophy, changes in mood, increased fatigue, insomnia, central weight gain, hot flashes and night sweats. Due to decreased hormone biosynthesis, LDL cholesterol is no longer utilized to the same degree leading to high LDL levels, abnormal HDL/LDL ratio and endothelial disfunction. Although we often look to ameliorate physical and mental symptoms of menopause, there are systemic consequences to low estradiol such as dyslipidemia and insulin resistance.

A common misconception is that since all phytoestrogens resemble estradiol that they all have the same effect in the body. However, we know that this not only isn’t true, but that there are multiple factors that affect their actions (or lack thereof), including the intestinal microbiome composition and individual genetic polymorphisms.

Specific phytoestrogens can target either a- or b-ERs which are found in different body tissues. Both types of receptors have different roles from each other and are found in different concentrations within different tissues.

Phytoestrogens do not increase estradiol levels, but typically act as estrogen modulators, and weak ones compared to endogenous estradiol. Meaning they can act as estrogen agonists or antagonists depending on endogenous levels of estrogen and other environmental factors.  This, combined with their metabolic mechanisms can help explain why some phytoestrogens work to relieve menopausal symptoms for some women but not others.

In this review we’ll discuss the role and outcomes of using isoflavones, prenylaflavonoids and lignans, found in soy, Hops and flaxseeds respectively, as well as their actions which go beyond activating ERs and include activation of multiple other signalling pathways.

Isoflavones: Soy

Isoflavones are phytoestrogens that are mainly found in soy but can be found in other legumes as well. The most highly researched isoflavones are genistein and daidzein.

Genistein has been shown to act on multiple different pathways that affect hormone and estrogen function. Like other phytoestrogens it targets ERs but also enzymes such as topoisomerase I and II, ATP-binding cassette transporters, protein tyrosine kinases, PPAR-g, mitogen-activated protein kinase (MAPK), 5-alpha reductase and protein histidine kinase.1

Genistein has also been shown to activate G protein-coupled estrogen receptors (GPERs) and influence epigenetic modifications that affect the regulation of cell proliferation and differentiation, therefore decreasing cancer risk.2

Additionally it can affect DNA methylation, histone modification and microRNA regulation. For example, in one study using an animal model of obesity, when pregnant mice were given genistein it induced DNA methylation in her offspring, changed the colour of their fur coat and decreased the incidence of obesity by adulthood.2

Overall, supplementing with soy isoflavones has shown varying effects in menopause. Soy isoflavones seem to have a higher affinity for b-ERs (versus a-ERs) which are more prevalent in adipose tissue, endothelial cells, the brain and kidneys.

Some studies show that it can reduce the frequency and severity of hot flashes in perimenopausal and menopausal women, but not in every case. One study showed that 30 mg genistein for 12 weeks reduced menopausal hot flashes by 51%, compared to 27% in the placebo group.1 But this hasn’t been a conclusive effect in all studies.

For other menopausal symptoms such as mood dysfunction, soy isoflavones can cross the blood-brain barrier and can bind to ERs in the brain hippocampus and therefore may have antidepressant effects.1

Other findings in the use of soy isoflavones, and especially genistein supplementation, is the positive effect on glucose metabolism and the reduction in both insulin levels and insulin resistance,2 which could help decrease adiposity and the risk of metabolic syndrome. One study showed that 54 mg genistein given to menopausal women resulted in lower fasting blood glucose, insulin and HOMA-IR after six months of treatment.1

Its effect on bone mineral density varies and doesn’t seem to have a particular protective effect on bone fracture incidence. However, many of these studies have been flagged as underpowered.

Part of this may also be due to the ability to convert dietary soy isoflavones to their active metabolites. Only about 30-40% of the population can convert daidzein to the active and potent metabolite S-equol.3 A major factor in conversion comes from the gut microbiome. Daidzein is metabolized by intestinal microbiota to either S-equal or the less potent O-desmethylangolensin (O-DMA). It’s been estimated that up to 60% of the population are non-producers of both S-equol and O-DMA, while the remainder primarily produce one or the other.3 Which leads us to the conclusion that consuming soy products doesn’t confer the same benefit in different individuals.

Interestingly, studies of the gut bacterial flora have identified a few bacterial species responsible for this conversion, including: Adlercreutzia equolifaciens, Eggerthella spp. and Slackia isoflavoniconvertens.3

Prenylflavonoids: Hops

Two of the most well-researched phytoestrogens from hops are 8-prenylnaringenin (8-PN) and xanthohumol (XH). Both can act as antioxidants scavenging free radicals and helping prevent the oxidation of LDL cholesterol, but 8-PN can also act as an aromatase inhibitor. However, similar to soy isoflavones, metabolism by gut bacteria is necessary to convert the isoxanthohumol from hops into 8-PN. One of the bacterial species responsible for this conversion was identified as Eubacterium limosum.4

Unlike soy isoflavones, 8-PN actually has a greater binding affinity for a-ERs which are mainly expressed in the endometrium, ovaries, bones and mammary glands. 8-PN can act as a selective estrogen receptor modulator (SERM) depending on the tissue of action.5

Due to its higher affinity for b-ERs, 8-PN seems to be the preferential phytoestrogenic compound for improving bone density. Animal studies have found that 8-PN enhances the inhibition of osteoclasts and increases osteoblast activity in vitro.5

In a prospective, double-blind, placebo-controlled trial of 67 menopausal women, using a standardized hop extract (100 mcg or 250 mcg) for 12 weeks led to significant decreases in Kupperman index scores (used to evaluate symptoms of menopause) compared to placebo.5

In another trial, 120 perimenopausal and menopausal women were supplemented with 500mg dried hops containing 100 mcg phytoestrogens for 90 days. Significant improvements in symptoms were reported in the hops group compared to placebo.5

Lignans: Flaxseed

Lignans are found most notably in flaxseeds, but are also found in whole grains, sesame seeds and legumes. Similar to other phytoestrogens, their estrogenic effect depends on the gut microbiome’s ability to convert lignans to enterodiol and enterolacton. One species of bacteria found responsible for this conversion is Eggerthella spp.2, though individual genetic polymorphisms can also affect the ability to benefit from this phytoestrogen.

In one study, 70 menopausal women were given 5 g flaxseed daily for two months and changes in menopausal symptoms scores were compared against a control group (untreated) as well as an experimental variable group of women who had begun HRT (2mg estradiol hemihydrate and 1 mg norethindrone acetate).6

Compared to the baseline, at the end of the treatment period those given flaxseeds had significantly improved menopausal symptoms scores (about 9-10% decrease in symptoms scores), whereas those in the control group had an increase in symptom scores by about 7%. Flaxseed treatment led to improvements in mental and physical health score averages and overall quality of life. These scores were decreased in the control group. Results of HRT use were similar to flaxseed with a 10% decrease in menopausal symptom scores.

Similar to other menopausal treatments including HRT, effects and outcomes depend on multiple factors and will differ from one individual to another. Genetic polymorphisms and gut microbiome composition play major roles in the ability to convert dietary phytoestrogens to their active compounds. As well, not all phytoestrogens are equal as they can have higher binding affinities for either a- or b-ERs, among influencing multiple other enzymes and signalling pathways.

However, the use of phytoestrogens as treatment provides an alternative to synthetic HRT and may not only help relieve symptoms of menopause such as hot flashes and depression, but may help lower the risk of cardiovascular disease, type 2 diabetes, and metabolic syndrome in menopausal women.

References

1. Thangavel P, Puga-Olguin A, Rodriguez-Landa JF, Zepeda RC. (2019). Genistein as potential therapeutic candidate for menopausal symptoms and other related diseases. Molecules. 24(21): 3892

2. Rietjens IMCM, Louises J, Beekmann K. (2017). The potential health effects of dietary phytoestrogens. Br J Pharmacol. 174(11): 1263-80

3. Kolatorova L, Lapcik O, Starka L. (2018). Phytoestrogens and the intestinal microbiome. Physiol Res. 67(Suppl. 3): S401-8

4. Bolton JL, Dunlap TL, Hajirahimkhan A, et al. (2019). The multiple biological targets of hops and bioactive compounds. Chem Res Toxicol. 32(2): 222-33

5. Stulikova K, Karabin M, Nestor J, Dostalek P. (2018). Therapeutic perspectives of 8-prenylnaringenin, a potent phytoestrogen from hops. Molecules. 23(3): 660

6. Cetisli NE, Saruhan A and Kivcak B. (2015). The effects of flaxseed on menopausal symptoms and quality of life. Holist Nurs Pract. 29(3): 151-7

About The Author

Dr. Sarah Zadek is a licensed naturopathic doctor in Ontario with a clinical focus on women’s health, endocrinology and fertility. Sarah graduated from Nipissing University with an honours degree in biology after completing her thesis on genetics, oxidative stress and immune function. Her working background includes 14 years in pharmacy. Sarah is also an author and has written for multiple publications across North America including the NaturalPath, Naturopathic News and Review (NDNR), Naturopathic Currents, and Eco Parent Magazine online. Dr. Sarah Zadek is a naturopathic doctor with Conceive Health, practicing at Lakeridge Fertility in Whitby, and is a technical writer for Advanced Orthomolecular Research (AOR).

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