Irilone

Irilone at a Glance

Irilone is a minor isoflavone found in red clover (Trifolium pratense) and in the rhizomes of Iris species. Structurally it is 5,4’-dihydroxy-6,7-methylenedioxyisoflavone — an isoflavone carrying a methylenedioxy bridge across the A-ring, which sets it apart from the better-known red-clover isoflavones biochanin A, formononetin, genistein and daidzein, none of which have that ring ^{4Reference 4PubChem Compound Summary: Irilone (CID 5 et al.National Center for Biotechnology InformationView study →}.

Its name comes from the genus Iris (as with irigenin and iridin), where it was first described; the more studied dietary source is red clover, in which it sits alongside the four main isoflavones as a smaller fraction ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}.

The literature on irilone is sparse, and almost all of it is cell-based. The two things that make it worth a page are (1) it is a genuine estrogen-receptor-alpha agonist that contributes meaningfully to the estrogenic potential of red-clover supplements ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}, and (2) it behaves as an unusual phytoprogestin, potentiating progesterone signalling in laboratory models ^{5,6Reference 5Lee JH et al. · 2018Irilone from Red Clover (Trifolium pratense) Potentiates Progesterone SignalingView study →Reference 6Austin JR et al. · 2021Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid ReceptorsView study →}. There are no human trials of the isolated molecule, and its safety flag is low, tempered by the estrogenic caution that applies to any phytoestrogen.

Irilone As A Phytoprogestin

The most distinctive finding about irilone is not its estrogen activity — shared, in kind, with most red-clover isoflavones — but that it potentiates progesterone signalling, a rare property among plant compounds.

In screening of red-clover extract, irilone was identified as one of a small set of phytoprogestins: compounds that, while not strongly binding the progesterone receptor themselves, amplified the effect of progesterone in endometrial and ovarian cancer cell lines ^{5Reference 5Lee JH et al. · 2018Irilone from Red Clover (Trifolium pratense) Potentiates Progesterone SignalingView study →}. Follow-up work found that irilone raised progesterone-receptor (PR) protein levels in T47D breast-cancer cells, and that this potentiation was blocked by estrogen-receptor antagonists — pointing to an estrogen-receptor-dependent mechanism — with additional signalling through the glucocorticoid receptor ^{6Reference 6Austin JR et al. · 2021Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid ReceptorsView study →}. Notably, in that study irilone did not trigger proliferation of mouse uterine cells, which the authors read as a potentially selective, tissue-specific action ^{6Reference 6Austin JR et al. · 2021Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid ReceptorsView study →}.

This is mechanistically interesting for women’s-health botanicals, but it must be read for what it is: cell-line and single mouse-model pharmacology, not a demonstrated clinical effect.

The Methylenedioxy Group & Metabolic Stability

Irilone’s A-ring methylenedioxy group is not just what distinguishes it structurally — it also changes how the body handles it. Where most isoflavones are extensively transformed by gut bacteria (genistein and daidzein are metabolised to compounds such as equol), irilone is largely resistant to degradation by the human gut microbiota: in vitro incubation with human faecal flora produced only a single minor metabolite, dihydroirilone, and the methylenedioxy ring appears to shield the molecule from bacterial breakdown ^{3Reference 3Braune A · 2010The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiotaView study →}.

This relative stability means a larger share of ingested irilone may survive to circulate intact than for the more familiar isoflavones — a plausibility argument for why a minor constituent could still contribute to a supplement’s overall estrogenic signal ^{1,3Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →Reference 3Braune A · 2010The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiotaView study →}. It has not been confirmed with human pharmacokinetic data.

What It's Used For

Irilone’s evidence is thin and almost entirely in vitro, but it splits into two coherent stories — an estrogenic one and a progestin-potentiating one — plus a weak antioxidant contribution as an extract constituent.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. All rows here rest on in-vitro data, so scores stay low; read the per-row basis.

01Estrogenic (ERα agonist)Shaky38%ERα cell assays + plasma-level modelling (~50% of daidzein’s E2 equivalents) ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}

02Progesterone-signalling potentiationShaky32%Endometrial/ovarian/breast cancer cell lines + one mouse uterine read-out ^{5,6Reference 5Lee JH et al. · 2018Irilone from Red Clover (Trifolium pratense) Potentiates Progesterone SignalingView study →Reference 6Austin JR et al. · 2021Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid ReceptorsView study →}

03Antioxidant (extract constituent)Shaky20%In-vitro, as one isoflavone among many in Iris/red-clover extracts ^{7Reference 7Ibrahim SRM et al. · 2017Ibrahim SRM, Mohamed GA, Zayed MF, Ross SA (2017). 8-Hydroxyirilone 5-methyl ether and 8-hydroxyirilone, new antioxidant and α-amylase inhibitors isoflavonoids from Iris germanica rhizomes. Bioorganic Chemistry. https://pubmed.ncbi.nlm.nih.gov/28069265/View study →}

Mechanisms

The load-bearing point is that irilone’s progestin-like effect is itself estrogen-receptor-dependent — the estrogenic and progestogenic stories are mechanistically linked, not separate.

Pharmacokinetics

Direct human pharmacokinetic data on irilone are absent. The one distinctive, well-documented pharmacokinetic feature is its resistance to gut-microbial degradation: in vitro, human faecal microbiota converted irilone only to a single minor metabolite, dihydroirilone, whereas isoflavones such as genistein are extensively transformed — the A-ring methylenedioxy group appears to block bacterial cleavage ^{3Reference 3Braune A · 2010The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiotaView study →}. This has been used to argue that a relatively larger fraction of ingested irilone may reach the circulation intact, but oral bioavailability, plasma half-life and tissue distribution have not been measured for the isolate ^{1,3Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →Reference 3Braune A · 2010The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiotaView study →}.

Clinical Trials

There are no clinical trials of isolated irilone. Human exposure occurs only within whole standardised red-clover extracts (studied for menopausal symptoms, bone and cardiovascular endpoints), where irilone is one minor isoflavone among several and is not the tested variable.

Last checked: July 2026.

Isolate vs. Plant Studies

Irilone sits at an informative midpoint. Its mechanistic pharmacology has been done on the isolated molecule — pure irilone was used to demonstrate ERα agonism ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →} and progesterone potentiation ^{5,6Reference 5Lee JH et al. · 2018Irilone from Red Clover (Trifolium pratense) Potentiates Progesterone SignalingView study →Reference 6Austin JR et al. · 2021Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid ReceptorsView study →}, which is a genuine strength for attributing those activities to the compound itself. But every human/whole-organism data point belongs to red-clover extract, not to irilone: the menopause, bone and cardiovascular literature is for the standardised extract (Promensil-type products, ~40–80 mg total isoflavones), within which irilone is a minor fraction ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}. So the mechanism is the molecule’s; the human outcomes are the plant’s. The estrogenic-contribution estimate — that irilone provides roughly half of daidzein’s estradiol-equivalents — is the one bridge between the two, and it is a modelled figure, not a measured clinical effect ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}.

Prevalence in Nature

Irilone occurs in two distinct botanical settings. It was first described in the rhizomes of Iris species (Iris germanica and relatives), the genus that gives the molecule its name and a rich source of methylenedioxy isoflavonoids ^{7Reference 7Ibrahim SRM et al. · 2017Ibrahim SRM, Mohamed GA, Zayed MF, Ross SA (2017). 8-Hydroxyirilone 5-methyl ether and 8-hydroxyirilone, new antioxidant and α-amylase inhibitors isoflavonoids from Iris germanica rhizomes. Bioorganic Chemistry. https://pubmed.ncbi.nlm.nih.gov/28069265/View study →}. Its more studied home is red clover (Trifolium pratense), where it is a minor aglycone alongside the dominant formononetin and biochanin A and the trace genistein/daidzein ^{8Reference 8Tsao R et al. · 2006Isoflavone profiles of red clovers and their distribution in different parts harvested at different growing stagesView study →}. In commercial red-clover dietary supplements irilone was measured at 1.8–10.9 mg per gram of capsule content, amounting to about 5–18% of the three major isoflavones — small in share but not negligible in estrogenic terms ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}. Content in the plant varies with cultivar, plant part (leaf tissue carries the highest isoflavone load) and growth stage ^{8Reference 8Tsao R et al. · 2006Isoflavone profiles of red clovers and their distribution in different parts harvested at different growing stagesView study →}, and validated UHPLC-MS/MS assays now quantify irilone as one of the routine red-clover isoflavone markers ^{2Reference 2Muchiri RN · 2020Single-Laboratory Validation of UHPLC-MS/MS Assays for Red Clover Isoflavones in Human Serum and Dietary SupplementsView study →}.

Discovery & Synthesis

Irilone was first reported from Iris rhizomes in the early 1970s, and its name — like irigenin, iridin and irisolone — derives directly from the genus Iris, the classic source of methylenedioxy isoflavonoids. It was later recognised as a constituent of red clover and drew renewed attention from the 2000s onward as one of the phytoestrogens contributing to red-clover menopause extracts ^{1,8Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →Reference 8Tsao R et al. · 2006Isoflavone profiles of red clovers and their distribution in different parts harvested at different growing stagesView study →}. Its structure is defined as 5,4’-dihydroxy-6,7-methylenedioxyisoflavone (C16H10O6, MW 298.25) — an isoflavone core bearing a 5-hydroxyl and a 4’-hydroxyl with a methylenedioxy bridge across the 6,7 positions of the A-ring ^{4Reference 4PubChem Compound Summary: Irilone (CID 5 et al.National Center for Biotechnology InformationView study →}. A dedicated total synthesis of irilone is not well documented in the accessible literature; the compound is obtained by isolation from Iris or red-clover material (increasingly via chromatographic fractionation of red-clover extract for research), rather than by commercial synthesis.

Patents: not yet researched.

Toxicity & Safety

Irilone carries a low toxicity flag. It is a normal dietary-exposure isoflavone — consumed for years as a minor component of red-clover supplements with no isolate-specific toxicity signal — and it is not mutagenic or acutely hazardous in any reported assay. The one caveat is not toxicity but hormonal activity: as a genuine estrogen-receptor agonist and progesterone-signalling potentiator, irilone shares the general phytoestrogen caution.

Safety at a Glance

✅ Low / no toxicity

• No isolate-specific toxicity reported. Consumed only as a minor fraction of established red-clover extracts; no mutagenicity or acute-toxicity signal in the available literature.
• Estrogenic activity. A confirmed ERα agonist that contributes to red-clover’s estrogenic potential — the standard phytoestrogen caution applies (hormone-sensitive conditions).
• Progesterone-signalling effects are cell-line data. The phytoprogestin findings come from cancer cell lines and one mouse model; they are not a demonstrated human effect and should not be read as either benefit or risk.
• No isolate safety dataset. No dedicated human pharmacokinetic, reproductive-toxicity or interaction data exist for pure irilone; whether-and-how it should be dosed alone is simply unstudied.

Estrogenic and reproductive considerations belong to the red-clover herb page and to any supplement product, where intake is actually decided — not to this molecule page. As a phytoestrogen, whole red-clover extract is generally cautioned in hormone-sensitive conditions; that caution extends to irilone as one of its estrogenic constituents ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}.

Dosage

There is no established dose for isolated irilone — it has never been given to humans as an isolate. Exposure occurs only through standardised red-clover extracts (commonly 40–80 mg total isoflavones per tablet), in which irilone is a minor fraction (roughly 1.8–10.9 mg/g of capsule content) ^{1Reference 1Lutter S et al. · 2014The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red cloverView study →}. These are the amounts present in research-grade supplements, not a personal recommendation.

References

1. Lutter S, Schmalbach K, Esch HL, Lehmann L (2014). The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red clover. Archives of Toxicology. https://pubmed.ncbi.nlm.nih.gov/23982890/
2. Muchiri RN, van Breemen RB (2020). Single-Laboratory Validation of UHPLC-MS/MS Assays for Red Clover Isoflavones in Human Serum and Dietary Supplements. Journal of AOAC International. https://pubmed.ncbi.nlm.nih.gov/33241325/
3. Braune A, Blaut M (2010). The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiota. Molecular Nutrition & Food Research. https://pubmed.ncbi.nlm.nih.gov/19998384/
4. PubChem Compound Summary: Irilone (CID 5281779), 5,4’-dihydroxy-6,7-methylenedioxyisoflavone, C16H10O6. National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/compound/5281779
5. Lee JH, Dean M, Austin JR, Burdette JE, Murphy BT (2018). Irilone from Red Clover (Trifolium pratense) Potentiates Progesterone Signaling. Journal of Natural Products. https://pubmed.ncbi.nlm.nih.gov/30199256/
6. Austin JR, Li K, Rivera Rodríguez R, Lantvit DD, Murphy BT, Burdette JE (2021). Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid Receptors. Journal of Natural Products. https://pubmed.ncbi.nlm.nih.gov/34813298/
7. Ibrahim SRM, Mohamed GA, Zayed MF, Ross SA (2017). 8-Hydroxyirilone 5-methyl ether and 8-hydroxyirilone, new antioxidant and α-amylase inhibitors isoflavonoids from Iris germanica rhizomes. Bioorganic Chemistry. https://pubmed.ncbi.nlm.nih.gov/28069265/
8. Tsao R, Papadopoulos Y, Yang R, Young JC, McRae K (2006). Isoflavone profiles of red clovers and their distribution in different parts harvested at different growing stages. Journal of Agricultural and Food Chemistry. https://pubmed.ncbi.nlm.nih.gov/16881680/

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