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Stigmasterol

Stigmasterol is a phytosterol, a class of plant-derived sterols with a tetracyclic structure similar to that of cholesterol. It has the molecular formula C₂₉H₄₈O and the systematic name (3''S'',8''S'',9''S'',10''R'',13''R'',14''S'',17''R'')-17-[(2''R'',5''S'')-5-ethyl-6-methylhept-3-en-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1''H''-cyclopenta[''[a'']phenanthren-3-ol (commonly known as stigmasta-5,22-dien-3''β''-ol).^[1] It occurs as a white solid with a characteristic odor, is insoluble in water but soluble in alcohols and other organic solvents, and has a melting point of 160–170 °C.^[1]^[2] Stigmasterol is abundant in plant cell membranes, where it contributes to fluidity and stability, analogous to cholesterol in animals. It is found in various sources, including vegetable oils (such as soybean and rapeseed, where it can comprise 10–20% of phytosterols), cereals, nuts, legumes, and certain medicinal plants like Annona muricata and Aegle marmelos. It is also present in some marine microalgae, such as Navicula incerta.^[3] Industrially, stigmasterol serves as a precursor for synthesizing progesterone and other steroid hormones, as well as vitamin D₃.^[1]^[3] In human nutrition, stigmasterol is absorbed in the gastrointestinal tract at lower rates than cholesterol (e.g., ~0.5% vs. ~59% in animal models) and can modulate serum lipid profiles by competing with cholesterol absorption. Research indicates potential health benefits, including cholesterol-lowering, anti-inflammatory, antioxidant, and anticancer effects, though further clinical studies on bioavailability and long-term safety are required. These properties have led to its use in functional foods and pharmaceutical applications.^[2]^[3]

Chemical characteristics

Molecular structure

Stigmasterol has the molecular formula C_{29}H_{48}O and a molecular weight of 412.71 g/mol.^[1]^[4] It possesses a tetracyclic structure characteristic of phytosterols, consisting of a steroid nucleus with four fused rings (A, B, C, and D) similar to that of cholesterol.^[5] The molecule features a hydroxyl group attached at the C-3 position in the A ring, a double bond between C-5 and C-6 in the B ring, and an additional double bond between C-22 and C-23 in the side chain.^[5] At C-17 of the D ring, an eight-carbon side chain is attached, incorporating an ethyl group at C-24 and methyl groups at C-10, C-13, and C-25.^[5]^[6] The stereochemistry of stigmasterol includes specific configurations at its chiral centers, notably a 3β-hydroxyl orientation and belonging to the 5α-series.^[5] Chiral centers are present at C-3 (S configuration), C-5, C-10, C-13, C-17, C-20, C-24, and C-25, with the double bond at C-22–C-23 exhibiting a trans orientation.^[5] In its three-dimensional conformation, the tetracyclic core adopts a largely planar arrangement, while the side chain remains flexible, contributing to the molecule's overall rigidity in the ring system.^[5] Compared to related sterols, stigmasterol differs from β-sitosterol by the presence of the C-22–C-23 double bond, which introduces an additional unsaturation in the side chain, whereas β-sitosterol has a fully saturated side chain.^[5] In contrast to campesterol, which features a methyl group at C-24 and lacks the C-22–C-23 double bond, stigmasterol has an ethyl substituent at C-24, making it a 24-ethylsterol with greater side-chain complexity.^[5]^[7]

Physical and chemical properties

Stigmasterol is a white crystalline solid at room temperature.^[8] It has a melting point of 170 °C.^[1] The specific optical rotation is -48° to -52° (c = 2, chloroform).^[9] Stigmasterol exhibits low solubility in water (practically insoluble; predicted ~0.027 mg/L), but it is soluble in organic solvents such as ethanol (~20 mg/mL with warming), chloroform (50 mg/mL), and dimethylformamide (~2 mg/mL).^[10]^[11]^[12] Chemically, stigmasterol demonstrates stability under neutral conditions and normal temperatures but is susceptible to oxidation, particularly at its double bonds, leading to products like 5α,6α-epoxystigmasterol.^[13] This compound absorbs ultraviolet light at a maximum wavelength of 226 nm in methanol, attributable to its conjugated double bond system.^[8] For analytical identification, stigmasterol is commonly detected using gas chromatography-mass spectrometry (GC-MS), where it typically elutes with a retention time of around 31–32 minutes under standard non-polar column conditions, showing a molecular ion at m/z 412.^[14] Nuclear magnetic resonance (NMR) spectroscopy reveals characteristic olefinic proton signals at δ 5.1–5.3 ppm for the Δ^{22} and Δ^5 double bonds.^[15]

History

Discovery and isolation

Stigmasterol was first isolated in 1906 by German chemists Adolf Windaus and Arthur Hauth from the oil extracted from Calabar beans (Physostigma venenosum), a plant native to West Africa.^[16] Their work, published in Berichte der Deutschen Chemischen Gesellschaft, identified stigmasterol as a novel component within the unsaponifiable fraction of the bean oil, distinguishing it from previously known sterols. This isolation represented a pivotal advancement in phytosterol research, as prior analyses of plant sterols had often treated them as homogeneous mixtures resembling cholesterol.^[16] The isolation process employed by Windaus and Hauth began with the saponification of the Calabar bean oil using alkaline hydrolysis to separate the sterol-containing unsaponifiable matter from glycerides and fatty acids.^[17] The crude sterol mixture was then acetylated to form sterol acetates, which were brominated to produce tetrabromide derivatives. Stigmasterol's acetate tetrabromide exhibited lower solubility compared to that of sitosterol, allowing for its selective precipitation and subsequent separation through fractional crystallization from solvents like ethanol.^[18] This bromination-crystallization technique exploited the structural differences in the sterols, particularly the additional double bond in stigmasterol at the C22-C23 position, which influenced the reactivity and solubility of its derivatives.^[16] Subsequent early efforts to isolate stigmasterol from other plant sources refined these methods, incorporating repeated fractional crystallizations of the free sterol or its esters to achieve higher purity.^[17] By the 1920s and 1930s, rudimentary chromatographic separations began to supplement crystallization, enabling better resolution from co-occurring phytosterols like sitosterol and campesterol in oils such as soybean and rapeseed. These milestones underscored stigmasterol's identity as a unique phytosterol of plant origin, featuring an ethyl side chain and unsaturation that set it apart from animal-derived cholesterol, paving the way for its recognition in broader biochemical contexts.^[16]

Early characterization

In the decades following its initial isolation, stigmasterol underwent detailed structural analysis using emerging analytical techniques of the era. Hydrogenation experiments in the 1930s and 1940s revealed that the compound absorbed two equivalents of hydrogen, establishing the presence of two isolated double bonds—one in the steroid nucleus at position C-5 and another in the side chain at C-22.^[19] Complementary ultraviolet (UV) spectroscopy confirmed the Δ5 double bond through characteristic absorption at approximately 240 nm, indicative of the α,β-unsaturated system in the B-ring.^[16] Degradative approaches in the 1950s further refined understanding of the side chain. Japanese chemist Kyosuke Tsuda and collaborators employed ozonolysis and subsequent derivatization of stigmasterol acetate to isolate and analyze fragments, elucidating the ethyl substituent at C-24 and its stereochemistry.^[20] These studies verified the trans (E) configuration at the C-22 double bond through comparison of optical rotations and chromatographic behavior of degradation products with known standards. The cumulative evidence from these degradative and spectroscopic investigations underpinned the formal nomenclature. By the mid-20th century, stigmasterol was designated as (22E)-stigmasta-5,22-dien-3β-ol in accordance with IUPAC conventions for unsaturated sterols, reflecting the stigmastane parent skeleton derived from early fragmentation analyses.^[1] Attempts at total synthesis during the 1960s, building on Tsuda's configurational work, provided additional validation of the proposed structure through partial constructions of the side chain and ring system.^[21]

Biological occurrence

Natural sources

Stigmasterol occurs abundantly in plant-based sources, particularly oilseeds and legumes, where it serves as a significant component of the phytosterol fraction. In soybean oil, stigmasterol concentrations reach approximately 87 mg/100 g, representing 17-21% of the total sterols, which typically range from 300-400 mg/100 g.^[22] Comparable levels are found in rapeseed oil (approximately 7–12 mg/100 g, or less than 1–2% of total sterols at 700-900 mg/100 g) and sunflower oil (approximately 39 mg/100 g).^[23]^[24] Among legumes, kidney beans contain about 41 mg/100 g, while peanuts exhibit lower amounts, around 3-4 mg/100 g in the whole nut.^[25] Concentrations are notably lower in fruits and vegetables, typically 1-10 mg/100 g; for instance, spinach holds about 1.1 mg/100 g, and zucchini around 8.4 mg/100 g.^[26] Stigmasterol distribution is predominant in oilseeds and legumes, with only trace levels (less than 5 mg/100 g) in nuts like hazelnuts and grains such as wheat.^[27] Environmental factors influence stigmasterol accumulation, with plant stress conditions—such as biotic or abiotic pressures—often elevating levels compared to healthy plants.^[28] In plants, stigmasterol primarily functions as a membrane sterol, modulating fluidity, permeability to water and ions, and overall membrane order, with content varying by species and typically higher in stressed individuals.^[29]

Biosynthesis pathway

Stigmasterol biosynthesis in plants occurs primarily through the mevalonate (MVA) pathway in the cytosol, initiating from acetyl-CoA and leading to the formation of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP). These building blocks condense sequentially to produce geranyl pyrophosphate, farnesyl pyrophosphate, and squalene, a linear C30 precursor. Squalene is then epoxidized to 2,3-oxidosqualene by squalene epoxidase (SQE), which serves as a rate-limiting step, before being cyclized into cycloartenol by the enzyme cycloartenol synthase (CAS). This cyclization marks the entry into the sterol-specific branch of the pathway, distinct from the cholesterol pathway in animals.^[30]^[5] From cycloartenol, a series of enzymatic modifications—including demethylations at C-4 and C-14, Δ8-Δ7 isomerization, and Δ24(28) reduction—progressively yield intermediates such as 24-methylene lophenol and obtusifoliol. Sterol C-24 methyltransferase (SMT1 and SMT2 isoforms) plays a crucial role by adding a methyl group at the C-24 position, directing the pathway toward C-28 and C-29 sterols; specifically, SMT2 facilitates the introduction of the C-24 ethyl group essential for β-sitosterol formation. β-Sitosterol then serves as the immediate precursor to stigmasterol, with the pathway branching at this point via desaturation. The distinctive C-22 double bond in stigmasterol, which differentiates it from β-sitosterol, is introduced in the final step.^[30]^[5]^[31] The key enzyme for this desaturation is the cytochrome P450 monooxygenase CYP710A (also known as sterol C-22 desaturase), which catalyzes the conversion of β-sitosterol to stigmasterol by inserting a double bond between C-22 and C-23 in the sterol side chain. This enzyme is conserved across plant species and represents a late-stage commitment to stigmasterol production. Mutants lacking functional CYP710A, such as in Arabidopsis thaliana, exhibit drastically reduced stigmasterol levels and altered membrane properties, underscoring its specificity in the pathway.^[30]^[5] Biosynthesis of stigmasterol is tightly regulated, particularly under abiotic stresses where it functions as a "stress sterol" to maintain membrane fluidity and integrity. Expression of CYP710A is upregulated in response to drought, salinity, and temperature fluctuations, leading to elevated stigmasterol accumulation; for instance, in Arabidopsis, AtCYP710A1 induction enhances tolerance to high temperatures by modulating plasma membrane permeability. Genetic variations further influence this pathway: in Arabidopsis, polymorphisms in CYP710A1 affect stigmasterol content and stress resilience, indirectly impacting plant growth and yield under adverse conditions. Similarly, in soybeans (Glycine max), natural genetic diversity in sterol biosynthetic genes, including those upstream like SQE1, alters phytosterol profiles (with stigmasterol as a major component), enhancing abiotic stress tolerance and seed yield in field trials under drought. Overexpression of such regulators, like GmNF-YC9 or GmSQE1, boosts sterol production and improves grain weight and count, demonstrating the pathway's role in agronomic performance.^[30]^[5]

Applications

Industrial extraction and production

Stigmasterol is primarily extracted on an industrial scale from soybean oil deodorizer distillate (SODD), a byproduct of soybean oil refining that contains sterol esters and free sterols.^[32] The process begins with saponification using alkali (such as potassium hydroxide in methanol or ethanol) to hydrolyze the sterol esters into free sterols, yielding a crude mixture where stigmasterol constitutes approximately 20-25% alongside other phytosterols like β-sitosterol and campesterol.^[33] This is followed by solvent extraction with alcohols (e.g., ethanol or isopropanol) to isolate the free sterols, achieving a total sterol recovery of 4-7% from SODD.^[34] Purification of stigmasterol from the crude sterol mixture involves methylation to form methyl esters for better separability, followed by chromatographic techniques such as high-performance liquid chromatography (HPLC) or counter-current chromatography, or alternatively solvent crystallization using solvents like acetone or hexane.^[35] These steps yield stigmasterol at 1-3% from the initial crude sterol mixture, with semi-synthetic modifications (e.g., hydrogenation or bromination-debromination) used to enhance purity beyond 95% by removing impurities like sitosterol isomers.^[17] Soybean-derived sources dominate due to their high stigmasterol content relative to other vegetable oils.^[36] Stigmasterol is produced industrially as part of the global phytosterols market, estimated at several thousand tons annually as of the 2020s, with major production concentrated in China and India, stemming from integrated operations that process millions of tons of SODD yearly into phytosterol fractions, with stigmasterol isolated for commercial applications.^[37]^[38] As of 2025, the stigmasterol-rich plant sterols market is projected to grow to USD 1,234.6 million by 2035 at a 3.8% CAGR.^[38] Quality control in industrial production adheres to United States Pharmacopeia (USP) and European Pharmacopoeia (EP) standards, ensuring stigmasterol purity exceeds 95% through assays for heavy metals, residual solvents, and microbial contaminants.^[39] Particular attention is given to minimizing oxidation products, such as hydroperoxides, via antioxidants during storage and inert atmosphere processing, as these can degrade bioactivity and compliance.^[40] Standardization involves gas chromatography-mass spectrometry (GC-MS) for composition verification, confirming low levels of contaminants like Δ7-stigmasterol or cholesterol traces.^[41]

Food and nutritional applications

Stigmasterol, as a component of phytosterol mixtures, is commonly incorporated into fortified foods such as margarines, yogurts, and spreads to increase dietary plant sterol intake. These products typically provide 1.5 to 3 grams of total plant sterols per day, with stigmasterol comprising a notable portion in blends derived from sources like soybean oil.^[42]^[43] This fortification mimics natural plant sterol consumption while aiming to support cholesterol management, as authorized by European Union regulations that permit health claims for up to 3 grams per day of plant sterols or stanols in reducing blood LDL-cholesterol by 7-12%.^[44]^[45] In dietary supplements, stigmasterol is available within phytosterol blends, often containing around 40% stigmasterol alongside beta-sitosterol and campesterol, formulated as capsules or powders for easy consumption.^[46] These supplements typically deliver 500 milligrams or more per serving to supplement natural intake. To enhance stability during food processing and storage, stigmasterol is frequently esterified with fatty acids, improving its solubility in fat-based products like spreads and dairy without compromising efficacy.^[47]^[48] In the nutritional context of Western diets, stigmasterol contributes to a typical daily plant sterol intake of 200-400 milligrams, primarily from vegetable oils, nuts, and grains.^[49]^[50] Its bioavailability is enhanced when consumed with dietary fats, as the lipid-soluble nature of stigmasterol allows better absorption in the presence of fatty acids from meals.^[51]^[52] This integration supports its role in everyday nutrition, where fortified foods and supplements can elevate intake to levels associated with cholesterol-lowering benefits under regulatory guidelines.^[44]

Pharmaceutical applications

Stigmasterol is incorporated into various pharmaceutical formulations, particularly as an excipient in lipid nanoparticle (LNP) systems to enhance stability and cellular uptake efficiency of drug cargoes, such as nucleic acids.^[53] Its derivatives, including stigmasteryl esters formed with fatty acids like myristic or oleic acid, are encapsulated in liposomes for improved gastrointestinal stability and targeted delivery, reducing oxidation products that could compromise efficacy.^[54] These esters also facilitate mitochondrial-targeted delivery in anti-inflammatory applications, leveraging stigmasterol's inherent properties to modulate cellular responses.^[55] In topical formulations, stigmasterol is used in creams to alleviate cutaneous allergic responses by inhibiting mast cell degranulation and inflammation at the application site.^[56] Phytosterols, including stigmasterol, serve as precursors for synthesizing boldenone undecylenate, an anabolic steroid approved for veterinary use to promote growth and treat muscular conditions.^[57] Emerging applications include its integration into nutraceutical formulations for osteoarthritis management, where doses of 100-200 mg have shown potential in preclinical models to reduce cartilage degradation when combined with regenerative therapies like mesenchymal stem cells.^[58] Emerging research as of 2025 explores its potential in modulating gut microbiota for antitumor effects and treating diabetic retinopathy.^[59]^[60] Stigmasterol holds Generally Recognized as Safe (GRAS) status from the FDA when used as part of plant sterol mixtures in food products, but pharmaceutical-grade applications demand rigorous purity testing to meet standards for excipients and active ingredients, typically exceeding 95% purity to avoid contaminants like oxidation byproducts.^[61] Patents exist for nanoemulsion and nanocrystal formulations of stigmasterol, which enhance oral bioavailability by increasing solubility in gastrointestinal fluids up to several-fold compared to the raw compound.^[62]^[63]

Health effects and research

Cholesterol-lowering effects

Stigmasterol exerts cholesterol-lowering effects primarily by interfering with intestinal cholesterol absorption. It competes with cholesterol for incorporation into mixed micelles in the intestinal lumen, thereby reducing the availability of cholesterol for uptake by enterocytes. This competition limits the solubilization and absorption of dietary and biliary cholesterol, promoting its fecal excretion.^[64] Additionally, stigmasterol downregulates key molecular pathways involved in cholesterol homeostasis. It suppresses the expression of the Niemann-Pick C1-like 1 (NPC1L1) transporter, a critical mediator of cholesterol influx in the small intestine, as demonstrated in cell models such as HepG2 hepatocytes where 100 μmol/L stigmasterol significantly reduced NPC1L1 mRNA levels. Stigmasterol also inhibits the sterol regulatory element-binding protein-2 (SREBP-2) pathway, which regulates genes for cholesterol synthesis and uptake, including HMG-CoA reductase; in animal studies, dietary stigmasterol at 0.5% reduced SREBP-2 activity by up to 44%, contributing to overall LDL cholesterol reductions of 8-12%. These mechanisms collectively lower circulating low-density lipoprotein (LDL) cholesterol without substantially altering high-density lipoprotein (HDL) levels.^[64]^[65] Clinical evidence supports stigmasterol's role within phytosterol mixtures for LDL reduction. Meta-analyses of randomized controlled trials indicate that consuming 2 g/day of phytosterols, including stigmasterol from sources like soy, lowers LDL cholesterol by approximately 10%, with effects observed across diverse populations. Specific trials on soy sterol esters, which contain stigmasterol alongside β-sitosterol and campesterol, have shown inhibition of cholesterol absorption and modest LDL reductions in hypercholesterolemic individuals, aligning with broader phytosterol data from 2010s studies. These benefits are dose-dependent, plateauing around 2-3 g/day.^[65]^[66]^[67] Regarding safety, stigmasterol supplementation in typical doses has no significant adverse impact on HDL cholesterol or overall lipid profiles in healthy individuals. However, in rare genetic cases of sitosterolemia, an autosomal recessive disorder impairing phytosterol excretion, elevated stigmasterol levels can accumulate, potentially exacerbating hypercholesterolemia and cardiovascular risk; thus, phytosterol intake is contraindicated for those affected.^[65]^[68]

Anti-inflammatory and antioxidant properties

Stigmasterol exhibits anti-inflammatory effects primarily through inhibition of key signaling pathways involved in immune response modulation. It suppresses the NF-κB pathway by downregulating p65 subunit activation and p-IκB-α phosphorylation, thereby reducing the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in lipopolysaccharide-stimulated macrophages and chondrocytes.^[69] Additionally, stigmasterol inhibits COX-2 expression and activity, limiting prostaglandin E2 production and subsequent inflammatory cascades in models of acute inflammation.^[70] These mechanisms contribute to decreased leukocyte infiltration and edema formation in experimental settings.^[71] In vivo studies demonstrate stigmasterol's efficacy in reducing inflammation across various animal models. Oral administration at doses of 5–30 mg/kg significantly attenuates carrageenan- or arachidonic acid-induced paw edema in mice and rats, with reductions ranging from 50% to 80% compared to controls, alongside lowered TNF-α levels.^[70] In collagen-induced arthritis rat models, 5 mg/kg daily dosing for 35 days decreases joint swelling by approximately 60%, suppresses pro-inflammatory mediators (including iNOS and COX-2), and elevates anti-inflammatory IL-10, without direct evidence of CRP modulation in humans.^[69] These findings highlight its potential in arthritis-like conditions through NF-κB and p38 MAPK inhibition.^[69] As of 2025, stigmasterol has also been shown to alleviate lipopolysaccharide (LPS)-induced mammary gland injury in animal models by inhibiting inflammation and ferroptosis pathways. Additionally, phytosterols including stigmasterol demonstrate therapeutic efficacy in digestive conditions such as peptic ulcer disease, inflammatory bowel disease (IBD), and liver failure induced by hepatotoxins.^[72]^[73] Regarding antioxidant properties, stigmasterol acts as a free radical scavenger, mitigating reactive oxygen species (ROS) accumulation despite lacking phenolic groups, possibly via structural mimicry that enhances membrane stability. It reduces lipid peroxidation markers like malondialdehyde (MDA) by 49–56% in Ehrlich ascites carcinoma-bearing mice at 5–10 mg/kg doses and in cerebral ischemia-reperfusion rat models at 20–80 mg/kg.^[70] In vitro assays show an IC₅₀ of 220 µg/mL for DPPH radical scavenging, supporting its role in upregulating endogenous antioxidants such as SOD and catalase.^[70] Specific applications include neuroprotection against Alzheimer's-related inflammation, where stigmasterol (doses not specified in models) attenuates microglial activation via AMPK-mediated NF-κB and NLRP3 suppression, reducing Aβ₄₂ levels and cognitive deficits in APPswe/PS1dE9 mice.^[74] For skin conditions, topical stigmasterol demonstrates anti-inflammatory activity by inhibiting ear edema in phorbol ester-induced dermatitis models and protecting against oxidative damage in skin carcinogenesis, with 200–400 mg/kg oral equivalents lowering MDA in mice.^[70]

Anticancer and other therapeutic potentials

Stigmasterol has demonstrated potential anticancer effects primarily through preclinical studies, where it inhibits tumor cell proliferation and induces programmed cell death. In various cancer cell lines, stigmasterol promotes apoptosis by activating caspase-3 and modulating Bcl-2 family proteins, leading to mitochondrial dysfunction and reactive oxygen species (ROS) accumulation.^[3] For instance, in breast cancer cells (MCF-7), stigmasterol enhances caspase-3 activity and downregulates anti-apoptotic Bcl-2 when combined with sorafenib, contributing to cell death at concentrations around 20 μM.^[76] Similarly, in prostate cancer cells, it triggers apoptosis via calcium overload in mitochondria, loss of membrane potential, and ROS production, with inhibitory effects observed at doses of 10-50 μM.^[77] These mechanisms extend to colon cancer, where stigmasterol suppresses proliferation and may prevent tumor development, though specific apoptotic pathways require further delineation.^[78] Beyond apoptosis, stigmasterol induces cell cycle arrest, particularly at the G2/M phase, halting cancer cell division. In gastric cancer models, treatment with 15-30 μM stigmasterol leads to G2/M accumulation, alongside reduced cyclin B1 and CDK1 expression, inhibiting progression through the cell cycle.^[79] This arrest, combined with apoptosis, results in IC50 values of 10-50 μM across breast, prostate, and colon cancer lines, indicating moderate potency in vitro.^[76] Recent 2020s studies highlight tumor suppression in xenograft models; for example, in BALB/c-nude mice bearing gastric tumors, stigmasterol (40 mg/kg) reduced tumor volume by inhibiting the Akt/mTOR pathway, promoting both apoptosis and protective autophagy.^[79] A 2022 study in breast cancer xenografts similarly showed decreased tumor growth via apoptosis induction.^[80] Stigmasterol's therapeutic potential extends to other conditions, including antidiabetic effects through PPARγ modulation. It acts as a PPARγ agonist, improving glycemic control by reducing fasting glucose and enhancing insulin sensitivity in diabetic rat models, with benefits observed at oral doses of 20-40 mg/kg.^[3] In anti-osteoarthritis applications, stigmasterol protects cartilage by inhibiting pro-inflammatory mediators like MMP-13 and ADAMTS-5, as well as cytokines such as IL-1β and TNF-α, in rodent models of joint degradation.^[81] These effects were confirmed in rabbit osteoarthritis models, where stigmasterol (1-5 mg/kg intra-articular) reduced cartilage loss and histological scores.^[82] Its antioxidant properties may indirectly support cancer prevention by mitigating oxidative stress in tumor microenvironments, though this overlaps with broader anti-inflammatory roles.^[3] Despite promising preclinical data, stigmasterol's clinical translation remains limited, with most evidence from in vitro and animal studies. Human trials are sparse, focusing mainly on bioavailability challenges due to its lipophilic nature and poor aqueous solubility, prompting calls for Phase II investigations to assess efficacy and dosing in cancer and metabolic disorders.^[76]

Role as a steroid precursor

Stigmasterol functions as a key precursor in the synthesis of boldenone, an anabolic steroid also known as Δ¹-testosterone, through biotransformation of phytosterols that include stigmasterol as a component.^[57] This process typically involves microbial fermentation, where bacteria such as Pseudomonas aeruginosa perform side-chain cleavage of the phytosterol to yield androstenedione, followed by reduction and dehydrogenation to boldenone.^[57] Boldenone, often esterified as boldenone undecylenate, is employed in veterinary medicine to promote growth in livestock like cattle.^[83] Optimized microbial methods achieve boldenone yields of 53.6% from corn oil phytosterols containing stigmasterol, with overall biotransformation efficiencies exceeding 90% in related fungal processes.^[57]^[84] The double bond at the C-22 position in stigmasterol's side chain enables selective chemical modifications, such as hydrogenation or oxidation, that support its conversion in synthetic routes.^[85] Historically, concerns arose in the 1970s regarding potential impurities from phytosterols like stigmasterol in boldenone formulations, contributing to regulatory scrutiny.^[86] In the context of sports doping, the World Anti-Doping Agency (WADA) prohibits boldenone and its derivatives, as dietary intake of stigmasterol-containing phytosterols may lead to detectable endogenous levels, complicating anti-doping tests.^[87]^[88] Beyond boldenone, stigmasterol serves as a starting material for progesterone synthesis via chemical degradation of its side chain, a method developed for industrial-scale production of this essential hormone.^[89] Further side-chain modifications of the resulting progesterone derivatives yield corticoid analogs, such as cortisol precursors, highlighting stigmasterol's versatility in steroid drug chemistry.^[90]

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[PDF] SUNF Sunflower Oil - Petfood Industry
Stigmasterol. 39.19 mg/100g. Internal Method. Trans. 0 g. B-sitosterol. 272.31 mg/100g. Internal Method. Polyunsaturated 3 g. Other Sterols. 251.05 mg/100g.
[25]
Peanuts as a Source of β-Sitosterol, a Sterol With Anticancer ...
Aug 9, 2025 · The results obtained in this work presented 44.31 mg of beta-sitosterol and 3.39 mg of stigmasterol per 100 g of roasted peanuts, in agreement ...
[26]
Spinach - COOKcal.Info
Jun 14, 2014 · Spinach ; Phytosterols ; Stigmasterol (mg). 1.1 ; Beta-sitosterol (mg). 5.2 ; Campesterol (mg). 0.9 ...
[27]
None
### Stigmasterol Concentrations in Foods
[28]
Why Do Plants Convert Sitosterol to Stigmasterol? - Frontiers
Mar 27, 2019 · Fluctuations in sitosterol and stigmasterol levels during development and stress conditions suggest their involvement in signaling activities ...Introduction · Impact of Biotic and Abiotic... · Potential Role for Stigmasterol...
[29]
Stigmasterol: An Enigmatic Plant Stress Sterol with Versatile Functions
Jul 25, 2024 · This comprehensive review provides an update on the biology of stigmasterol, particularly the physicochemical properties of this ethylsterol ...
[30]
https://doi.org/10.3389/fpls.2019.00354
[31]
https://doi.org/10.1105/tpc.105.036012
[32]
[PDF] Process for the production of Phytostanols from soybean oil ... - ijsar
The present study brought out an innovative integrated process for the isolation of phytostanols from SODD. Process simplicity, product quality, less residue ...
[33]
Recovery of phytosterols from waste residue of soybean oil ...
This study describes a catalytic decomposition and crystallization process to recover phytosterols from the waste residue of soybean oil deodorizer distillate ...Missing: stigmasterol | Show results with:stigmasterol
[34]
Optimization of Phytosterols Recovery from Soybean Oil Deodorizer ...
Feb 8, 2012 · The sterol yield obtained under the optimized conditions was 6.64%. This value is much greater than 4.43% obtained by the traditional industrial ...Missing: stigmasterol | Show results with:stigmasterol
[35]
Separation and purification of stigmasterol and β-sitosterol from ...
The separation and purification of stigmasterol and β-sitosterol from phytosterol mixtures by solvent crystallization method was studied
[36]
[PDF] Scientific Opinion on the safety of stigmasterol-rich plant sterols as ...
Increased plant sterol and stanol levels in brain of Watanabe rabbits fed rapeseed oil derived plant sterol or stanol esters. British Journal of Nutrition ...<|control11|><|separator|>
[37]
Global Phytosterols Market Report 2023: Sector to Reach $560 ...
Mar 20, 2023 · The global market for phytosterols is estimated at 23.8 thousand metric tons, valued at US$483 million, in 2022, the volume demand for ...Missing: per | Show results with:per
[38]
Advances and Challenges in Plant Sterol Research - PubMed Central
In fact, large-scale industrial PS bioconversion to key androstane-type synthons has already been introduced in Germany, USA, China, India, among others [17].
[39]
Stigmasterol, CAS No. 83-48-7 | More Reference Substances
Type analysis. Appearance, white to off-white powder. Purity (HPLC), ≥95 %. Loss on drying, ≤2.0 %. Heavy metals (as Pb), ≤0.001 %. Customers were also ...
[40]
Determination of stigmasterol primary oxidation products by high ...
Stigmasterol was used as a model compound. Hydroperoxides were obtained by photo-oxidation in dichloromethane in the presence of methylene blue as a sensitizer.Missing: historical | Show results with:historical
[41]
Gas Chromatographic Analysis of Plant Sterols - AOCS
The TMS-ethers are known to hydrolyze over time, so they should be analyzed within a few days. Although the derivatization reagents elute early and do not ...
[42]
Plant sterol and stanol margarines and health - PMC - NIH
The fortified margarines contain 2 g of plant sterols or stanols per daily portion. About 0.25 g of plant sterols and 0.3 g of cholesterol occur naturally ...
[43]
Stigmasterol-Rich Plant Sterols Market Demand 2025 to 2035
Apr 8, 2025 · By 2025, global market for plant sterols containing substantial amount of stigmasterol is expected to be valued at USD 850.2 million after registering a growth ...Missing: per | Show results with:per
[44]
Plant Sterols and Stanols and Blood Cholesterol - EFSA
May 16, 2012 · 1.5 - 3.0 g plant sterols/stanols per day and lowering blood LDL-cholesterol by 7 - 12 % and reduced risk of (coronary) heart disease.
[45]
[PDF] amending Regulations (EC) No 983/2009 and (EU) No
Jun 21, 2014 · The Authority also noted in its assessment that plant sterols and plant stanols at daily intakes ranging from 1,5 to 3 g have a similar efficacy ...
[46]
https://nutrikey.net/products/plant-sterols-60ct
[47]
Phytosterols | Linus Pauling Institute | Oregon State University
Esterification makes plant sterols and stanols more fat-soluble so they are easily incorporated into fat-containing foods, including margarines and salad ...
[48]
Phytosterol esters (Plant Sterol and Stanol Esters) - IFST
The enrichment of foods such as margarines with plant sterols and stanols is one of the recent developments in functional foods to enhance the cholesterol ...
[49]
Stigmasterol - an overview | ScienceDirect Topics
Phytosterol composition and content of olive oil are affected by cultivar, cropping year, degree of fruit ripeness, storage time of fruits before oil extraction ...
[50]
Intake of dietary plant sterols is inversely related to serum ... - Nature
Mar 31, 2004 · Plant sterol intake. Plant sterols are generally consumed in an amount of 200–400 mg/day in Western diets (Jones et al, 1997), but diets ...
[51]
Phytosterols: From Preclinical Evidence to Potential Clinical ...
... stigmasterol had the lowest bioavailability. Beverages with higher fat content (2.4%) revealed higher PS bioavailability (31.4% and 28.2%, respectively) ...
[52]
Stigmasterol - Structure, Food Sources, Supplements, and Health ...
Oct 31, 2024 · Soybean oil (36mg) and rapeseed oil (12.3mg) are among the best natural sources of stigmasterol, often used in cooking or food products (9) (10 ...
[53]
https://kyforabio.com/products/stigmasterol-14497
[54]
Stigmasterol and its esters encapsulated in liposomes
Feb 15, 2025 · Another autoxidation pathway is through the sterol's Δ5,6 double bond, which can form α- and β-epoxysterol intermediates, which is then ...
[55]
Phytosterol organic acid esters: Characterization, anti-inflammatory ...
Feb 26, 2024 · Stigmasteryl phenolates have better suitability for food processing than stigmasterol. Stigmasteryl phenolates showed more bio-accessible than ...
[56]
Stigmasterol Alleviates Cutaneous Allergic Responses in Rodents
Skin histopathology of injected sites confirmed that stigmasterol reduced mast cell trafficking and degranulation associated with C48/80-induced pruritus.
[57]
Stigmasterol | chemical compound | Britannica
Stigmasterol, which is readily obtainable from soybean oil, can be transformed easily to progesterone and to other hormones, and commercial processes based on ...
[58]
A novel therapeutic combination of mesenchymal stem cells ... - NIH
Mar 23, 2021 · The present study provides valuable insights in situ using a combination of hPMSCs and stigmasterol towards cartilage repair and regeneration.
[59]
Plant sterols/Plant sterol esters - GRAS Notices - FDA
Intended Use: Plant sterols as an ingredient in vegetable oil spreads, dressings for salad, health drinks, health bars, yogurt-type products at a level of 1 ...
[60]
Nanocrystals as Tool to Enhance Stigmasterol Oral Bioavailability
When formulated as nanocrystals, the solubility of stigmasterol in water and in simulated gastro-intestinal fluids was boosted compared to the raw material. The ...
[61]
CN100556921C - A preparation method of stigmasterol molecularly ...
... Stigmasterol is shown special preferably absorption property. There is the binding site of determining arrangement in the opening structure that the ...
[62]
Phytosterols: Physiological Functions and Potential Application - MDPI
The NPC1L1 expression in HepG2 cells was significantly reduced after treatment with 100 μmol/L sitosterol or stigmasterol [37]. Free phytosterols can increase ...
[63]
Phytosterols in the Treatment of Hypercholesterolemia and ... - NIH
There is consistent evidence that the intake of phytosterols (2 g/day) is associated with a significant reduction in LDL-cholesterol (8 - 10%). However ...
[64]
https://www.mdpi.com/2304-8158/13/11/1754
[65]
Soy sterol esters and β-sitostanol ester as inhibitors of cholesterol ...
The present study showed that soy sterol ester and β-sitostanol ester inhibited cholesterol absorption, although there were no major changes in sterol ...
[66]
Sitosterolemia: a review and update of pathophysiology, clinical ...
It is clear that plant sterols are toxic to those with sitosterolemia, but plant sterol intake seems to be safe to nonsitosterolemic individuals. Instead, plant ...
[67]
https://www.sciencedirect.com/science/article/pii/S000291652307096X
[68]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4835564/
[69]
https://doi.org/10.1016/j.intimp.2020.106642
[70]
https://doi.org/10.3390/antiox11101912
[71]
Advances in Stigmasterol on its anti-tumor effect and mechanism of ...
Dec 12, 2022 · It has anti-tumor activities by regulating multiple biological behaviors of tumor cells such as apoptosis, proliferation, metastasis ...
[72]
Stigmasterol Induces Cell Apoptosis in Prostate Cancer by Calcium ...
Background: Stigmasterol has been reported to inhibit the growth and proliferation of various cancer types, including prostate cancer.
[73]
Stigmasterol - an overview | ScienceDirect Topics
Stigmasterol is a ubiquitous phytosterol found in many medicinal plants. It shows numerous biological activities like anticancer, anti-inflammatory, anti- ...
[74]
Stigmasterol Simultaneously Induces Apoptosis and Protective ...
Feb 22, 2021 · Our findings illustrate for the first time that SS simultaneously induces apoptosis and protective autophagy by inhibiting Akt/mTOR pathway in gastric cancer ...Missing: IC50 | Show results with:IC50
[75]
The inhibitory role of stigmasterol on tumor growth by inducing ...
Jun 20, 2022 · Human breast cancer cell ... Stigmasterol causes ovarian cancer cell apoptosis by inducing endoplasmic reticulum and mitochondrial dysfunction.Missing: cycle arrest colon IC50
[76]
Stigmasterol: a phytosterol with potential anti-osteoarthritic properties
This study shows that stigmasterol inhibits several pro-inflammatory and matrix degradation mediators typically involved in OA-induced cartilage degradation.Missing: CRP | Show results with:CRP
[77]
Health Benefits and Pharmacological Properties of Stigmasterol
Regarding oxidative stress, stigmasterol treatment at doses of 5 and 10 mg/kg to mice with EAC decreased lipid peroxidation levels by 49.0% and 56.1%, ...
[78]
Single step biotransformation of corn oil phytosterols to boldenone ...
May 26, 2016 · Highlights. •. Biotransformation of crude corn oil phytosterols to 4-androstene-3, 17-dione, testosterone and boldenone.
[79]
Urine levels of boldenone and phytosterols in 10 healthy human...
Stigmasterol is precursor of anabolic steroid boldenone. Boldenone undecylenate is commonly used in veterinary medicine to induce growth in cattle, but it ...
[80]
Boldenone and Testosterone Production from Phytosterol via One ...
Testosterone (TS) and its 1(2)-dehydrogenated derivative boldenone (BD) are widely used in medicine, veterinary science and as precursors in organic synthesis
[81]
A comprehensive update on phytochemistry, analytical aspects ...
Stigmasterol has various biological effects, including antioxidant, anticancer, antidiabetic, respiratory diseases, and lipid-lowering effects.
[82]
[PDF] BOLDENONE HISTORY in BELGIUM - RIVM
Stigmasterol: 5 %. Heinemann et al., Eur J Clin Invest 23 (12)(1993) 827-31. Q ... Microorganisms from the'soibum exudate' involved in microbial bioconversion of ...Missing: conversion | Show results with:conversion
[83]
[PDF] international standard - prohibited list - WADA
The Prohibited List is a mandatory International Standard as part of the World. Anti-Doping Program. The List is updated annually following an extensive ...Missing: stigmasterol | Show results with:stigmasterol
[84]
(PDF) Excretion of endogenous boldione in human urine
Aug 9, 2025 · The list of prohibited substances of the World Anti-Doping Agency (WADA) classifies the administration of several steroids in sports as doping.
[85]
A convenient synthesis of progesterone from stigmasterol
A comprehensive update on phytochemistry, analytical aspects, medicinal attributes, specifications and stability of stigmasterol.Missing: corticoids | Show results with:corticoids
[86]
A comprehensive update on phytochemistry, analytical aspects ...
Numerous hormones, including estrogen, progesterone, corticoids and androgen, are synthesized by stigmasterol.