Soy and red clover are often grouped together as sources of isoflavones and treated as though they were interchangeable. They belong to the same chemical family, but their dominant compounds are different. That difference affects how they interact with estrogen receptors, how they are processed by gut bacteria and why the same amount of isoflavones may not produce the same response in every person.
This article looks at those differences in detail. It covers the molecules found in each plant, the additional metabolic step involved with red clover, the role of equol production and why research conducted on soy should not automatically be applied to red clover.
Same family, different members
The main isoflavones in soy are genistein and daidzein, with glycitein present in smaller amounts. In the bean, these compounds are stored largely as glucosides such as genistin and daidzin, along with their malonyl esters.
Red clover has a different profile. Its dominant isoflavones are formononetin and biochanin A.
In a genotype survey of Trifolium pratense at flowering, formononetin accounted for approximately 51% of total isoflavones and biochanin A for around 40%. Together, they represented about 91% of the measured isoflavones.
Genistein was present at approximately 0.36–0.59 mg/g of dry matter, while daidzein was measured at only 0.06–0.14 mg/g.
Red clover therefore contains genistein and daidzein, but they are present in much smaller amounts than formononetin and biochanin A.
The relationship between these compounds is chemically specific.
- Formononetin is the 4′-O-methyl ether of daidzein.
- Biochanin A is the 4′-O-methyl ether of genistein.
The structural difference comes from a methyl group attached to the hydroxyl group at the 4′ position of the B-ring.
For a more detailed look at red clover chemistry, including glycoside forms, measured concentrations and other compounds found in the plant, see The Isoflavones in Red Clover: Formononetin, Biochanin A and the Rest.
The methyl group and what the gut does with it
That methyl group affects how the molecules interact with estrogen receptors.
In the characterisation of a clinical red clover extract by Booth and colleagues, competitive binding assays gave genistein an IC50 of approximately 0.020 μM at ERβ, while daidzein had an IC50 of around 1.2 μM.
Their methylated counterparts showed considerably weaker binding. Biochanin A had an IC50 of approximately 4.1 μM, while formononetin was around 60 μM. Formononetin also showed no estrogenic activity in the cell-based assay conducted alongside the binding study.
The two dominant isoflavones in red clover therefore have relatively weak receptor activity in their original methylated forms.
Their importance in phytoestrogen research becomes clearer once metabolism is taken into account.
Gut microbiota can demethylate formononetin to daidzein and biochanin A to genistein. This conversion produces compounds with stronger estrogen-receptor activity.
Research by Presto Åkerfeldt and colleagues described these metabolic pathways in red clover. Formononetin was converted to daidzein and could then continue toward equol formation. Biochanin A was converted to genistein and could also be metabolised into the non-estrogenic compound p-ethylphenol.
There is an important limitation to that study. It was conducted in pregnant sows fed red clover silage rather than in humans. Pig and human gut microbiota share some characteristics, but they are not identical. The study is useful for illustrating the metabolic pathway, but it does not establish how much of the same conversion occurs in people.
Red clover can therefore be understood as a source of precursor compounds. Soy supplies relatively high amounts of genistein and daidzein directly, whereas red clover supplies mainly formononetin and biochanin A, which first require microbial demethylation.
That additional metabolic step introduces another source of variation between individuals.
The equol story: why it does not work the same for everyone
Daidzein can undergo another important transformation in the gut.
Whether daidzein comes directly from soy or is produced through the metabolism of formononetin from red clover, certain intestinal bacteria can convert it into equol.
Equol has a higher affinity for estrogen receptors than daidzein. It has attracted considerable research attention because it may contribute to some of the biological effects associated with daidzein-containing foods and supplements.
The important point is that not everyone produces equol.
Equol production depends on the presence of particular gut bacteria. People with the necessary microbial communities are commonly described as equol producers.
Those without these bacteria process daidzein differently and may excrete much of it without converting it to equol.
Published estimates suggest that approximately 25–60% of people possess gut microbial communities capable of producing equol. The percentage is generally reported to be higher in Asian populations than in Western populations, and dietary habits may also be associated with these differences.
In the study by Frankenfeld and colleagues, adults were given a three-day soy challenge. A clear majority of the participants were classified as equol non-producers.
This distinction matters when interpreting studies of isoflavones.
Within the same trial, some participants may convert daidzein into a metabolite with greater estrogen-receptor affinity while others may not. If a study does not separate participants according to equol-production status, its average result combines people with different metabolic responses.
This may help explain some of the variability seen across the isoflavone literature.
It also means that one person's response to an isoflavone preparation does not necessarily predict another person's response. Part of the difference may come from the individual's gut microbiota rather than from the product itself.
Equol is not the only possible metabolite.
Daidzein can also be converted into O-desmethylangolensin. Estimates suggest that approximately 80–95% of people may have the capacity to form this metabolite.
Pfitscher and colleagues have suggested that metabolites other than equol may also contribute to the activity associated with red clover isoflavones. However, human data on their formation and bioavailability remains too limited for firm conclusions.
For more background on how phytoestrogens interact with estrogen receptors, see Phytoestrogens 101.
Why soy research does not transfer directly to red clover
Research conducted on soy should not automatically be treated as evidence for red clover. There are several reasons.
Different starting molecules
Soy primarily supplies genistein and daidzein.
Red clover primarily supplies formononetin and biochanin A, which are the 4′-O-methyl ethers of daidzein and genistein.
The receptor-binding data show that these compounds do not behave identically in their original forms.
An additional metabolic step
The dominant isoflavones in red clover must undergo demethylation before they become daidzein and genistein.
This process depends partly on gut microbiota and can vary between individuals.
Soy already contains substantial amounts of genistein and daidzein, so those compounds do not require the same initial conversion.
Different minor compounds
Red clover also contains compounds that are not prominent features of the typical soy isoflavone profile.
These include irilone, pratensein, pseudobaptigenin, prunetin and calycosin, along with coumestans such as coumestrol and pterocarpans such as maackiain.
One characterised clinical red clover extract contained approximately 3.2% irilone.
Research by Braune and colleagues found that irilone was largely resistant to degradation by human gut microbiota. Genistein, by comparison, was readily metabolised by faecal microbiota from all ten donors included in the study.
This illustrates how structurally related isoflavones can behave quite differently during intestinal metabolism.
Different preparations and research settings
Much of the soy research literature examines whole foods and dietary exposure across populations.
Red clover research, by comparison, focuses largely on concentrated extracts supplied at defined doses.
These represent different forms of exposure.
Commercial red clover preparations have also been shown to vary considerably in their measured isoflavone content. Research has found that the surrounding product matrix can influence the intestinal disposition of these compounds in experimental models.
None of these differences makes red clover inherently better or worse than soy.
They simply mean that each plant should be evaluated using evidence generated from the plant and preparation actually being studied.
Practical implications
Look at the marker compounds, not only the plant name
The word “isoflavones” does not describe a single chemical composition.
A soy extract standardised to genistein and daidzein is chemically different from a red clover extract standardised to formononetin and biochanin A.
A percentage therefore becomes meaningful only when it is clear which compounds were measured.
Individual responses can vary
Differences in gut microbiota provide a well-documented reason why the same isoflavone preparation may be metabolised differently by different people.
Equol production is one example. The demethylation of formononetin and biochanin A introduces another potential source of variability.
For this reason, the same preparation should not be expected to produce an identical response in everyone.
Keep topical and oral use separate
Demethylation and equol production take place through intestinal metabolism.
These processes are relevant to orally consumed products.
A cosmetic applied to the skin follows a different route of exposure, so findings about gut metabolism should not automatically be applied to topical skincare.
Check what was actually measured
Reported isoflavone concentrations can differ according to the analytical method used.
Some laboratories hydrolyse samples and report values as aglycone equivalents. Others measure compounds in their native glycoside forms.
Plant part, cultivar and growth stage can also influence the resulting isoflavone profile.
For more detail on red clover chemistry, see The Isoflavones in Red Clover.
For a broader look at the skin and hair research, see Red Clover: The Anatolian Flower Science Keeps Coming Back To.
For information about how Minerva108 works with red clover, see our red clover ingredient page.
Frequently asked questions
Is red clover the same as soy isoflavones?
No. Their dominant isoflavones are different.
Soy is dominated by genistein and daidzein, while red clover is dominated by formononetin and biochanin A.
Formononetin is the 4′-O-methyl ether of daidzein, while biochanin A is the 4′-O-methyl ether of genistein.
Red clover contains genistein and daidzein in smaller amounts. In one survey conducted at flowering, daidzein was measured at 0.06–0.14 mg/g of dry matter compared with 2.61–4.40 mg/g for formononetin.
What is an equol producer?
An equol producer is someone whose gut microbiota can convert daidzein into equol.
Equol is a metabolite with higher estrogen-receptor affinity than daidzein itself.
Estimates suggest that approximately 25–60% of people possess the gut bacteria required for this conversion, with higher percentages generally reported in Asian populations than in Western populations.
People without the necessary microbial communities process daidzein differently and may excrete much of it without converting it to equol.
Why do isoflavones seem to work for some people and not others?
Differences in metabolism are one possible explanation.
Only a proportion of people can produce equol from daidzein. A study that does not separate participants according to equol-production status may therefore combine people with different metabolic responses.
In the case of red clover, the microbial conversion of formononetin and biochanin A adds another metabolic step that may also vary between individuals.
These differences can contribute to variation in response.
Can I use soy isoflavone research to judge red clover?
Not directly.
The dominant starting molecules differ, and red clover requires an additional microbial demethylation step before much of its formononetin and biochanin A becomes daidzein and genistein.
The two plants also differ in their minor compounds.
Irilone, for example, has been shown to resist degradation by human gut microbiota, while genistein is more readily metabolised.
The research formats differ as well. Soy studies frequently examine whole foods and dietary exposure, while red clover studies more commonly investigate concentrated extracts.
Findings therefore need to be interpreted according to the specific plant and preparation that was actually studied.
Which is better, red clover or soy?
Neither can be described as categorically better.
They have different isoflavone profiles and have been studied in different forms and contexts.
More useful questions are which marker compounds an extract is standardised to, which plant part was used, how the extract was prepared and whether the intended use is oral or topical.
Findings related to gut metabolism apply to orally consumed products and should not automatically be extended to cosmetics applied to the skin.
This article is for general information and education only. It is not medical advice, and nothing here is intended to diagnose, treat, cure or prevent any disease. If you are pregnant, breastfeeding, taking medication or managing a health condition, speak with a healthcare professional before using red clover or soy isoflavone supplements.
References
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- Braune A, Maul R, Schebb NH, Kulling SE, Blaut M. The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiota. Molecular Nutrition & Food Research, 2010;54(7):929–938. doi.org/10.1002/mnfr.200900233
- Booth NL, Overk CR, Yao P, et al. The chemical and biologic profile of a red clover (Trifolium pratense L.) phase II clinical extract. Journal of Alternative and Complementary Medicine, 2006;12(2):133–139. doi.org/10.1089/acm.2006.12.133
- Setchell KDR, Clerici C. Equol: history, chemistry, and formation. The Journal of Nutrition, 2010;140(7):1355S–1362S. doi.org/10.3945/jn.109.119776
- Frankenfeld CL, Atkinson C, Wähälä K, Lampe JW. Obesity prevalence in relation to gut microbial environments capable of producing equol or O-desmethylangolensin from the isoflavone daidzein. European Journal of Clinical Nutrition, 2014;68(4):526–530. doi.org/10.1038/ejcn.2014.23
- Pfitscher A, Reiter E, Jungbauer A. Receptor binding and transactivation activities of red clover isoflavones and their metabolites. Journal of Steroid Biochemistry and Molecular Biology, 2008;112(1–3):87–94. doi.org/10.1016/j.jsbmb.2008.08.007
- Lemežienė N, Padarauskas A, Butkutė B, Cesevičienė J, Taujenis L, Norkevičienė E. The concentration of isoflavones in red clover (Trifolium pratense L.) at flowering stage. Zemdirbyste-Agriculture, 2015;102(4):443–448. doi.org/10.13080/z-a.2015.102.057
- Wang SW, Chen Y, Joseph T, Hu M. Variable isoflavone content of red clover products affects intestinal disposition of biochanin A, formononetin, genistein, and daidzein. Journal of Alternative and Complementary Medicine, 2008;14(3):287–297. doi.org/10.1089/acm.2007.0617
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