Phytosterols

Phytosterols

1. Identity: Chemical Nature, Nomenclature, and Forms

Phytosterols are a kind of plant metabolite belonging to the triterpene family. They are naturally found plant-based steroidal compounds which constitute the most significant percentage of unsaponifiable lipid content in plants, and are structurally related to cholesterol, containing a steroid backbone with a hydroxyl group at C-3 and an aliphatic chain at C-17, unlike animal sterols. Phytosterols have a double bond within the steroid nucleus, like cholesterol; however, phytosterols also may comprise a substituted side chain at C-24, such as an ethyl or methyl group, or an additional double bond.

More than 250 phytosterols have been identified in botanical sources, with β-sitosterol being the most commonly reported. β-Sitosterol, campesterol, and stigmasterol are the main phytosterols found in plants. Well-known examples of phytosterols include 4-desmethylsterols (e.g., β-sitosterol, campesterol, stigmasterol, brassicasterol, 22-dehydrobrassicasterol, and Δ5-avenasterol), 4-monomethyl sterols, and 4,4-dimethyl sterols (triterpene alcohols) such as cycloartenol, 24-methylenecycloartanol, and cyclobranol.

Closely related to phytosterols are phytostanols: phytostanols are saturated sterol alcohols present in only trace amounts in nature and may also be synthetically produced, such as by hydrogenation of phytosterols. Examples of phytostanols include β-sitostanol, campestanol, cycloartanol, and saturated forms of other triterpene alcohols.

Phytosterols exist in multiple chemical forms in plant tissue. They can exist in plants as free form, as esters with fatty acids, as glycosides, or as acylated steryl glycosides. Naturally occurring phytosterols primarily exist in three chemical forms: free, esterified (and glycosylated). For supplemental and functional-food purposes, phytosterol esters are of particular commercial relevance because free phytosterols are highly hydrophobic and poorly soluble in the gastrointestinal tract. Phytosterols are highly hydrophobic, do not dissolve to any significant degree in the micellar phase in the digestive tract, and therefore are not capable of efficiently blocking cholesterol absorption; oils and fats dissolve free phytosterols only to a limited degree, and since only solubilized phytosterols inhibit the absorption of cholesterol, this "delivery" problem must be adequately addressed. Esterification with fatty acids substantially improves solubility in fatty food matrices, which is the basis for phytosterol-enriched spreads and margarines. Benecol spread, the first phytosterol-enriched functional food, had been sold in Finland in 1995, followed by the launching and approval (via the US FDA and many international counterparts) of several other phytosterol and phytostanol-enriched foods in the US and EU in 2000.

2. Natural Sources and Dietary Occurrence

Phytosterols are found in all plant foods, but the highest concentrations are found in unrefined plant oils, including vegetable, nut, and olive oils. Nuts, seeds, whole grains, and legumes are also good dietary sources of phytosterols.

Among specific food sources, measured phytosterol content varies considerably by food type and processing state. Sesame seed and wheat germ had the highest total phytosterol content (400–413 mg/100 g) and Brazil nuts the lowest (95 mg/100 g). Of the products typically consumed as snack foods, pistachio and sunflower kernel were richest in phytosterols. Pistachio and sunflower kernel contain 270–289 mg/100 g; β-sitosterol, Δ5-avenasterol, and campesterol are predominant. Among edible oils, rice bran oil leads with nearly 1,900 mg per 100 grams, followed by corn oil at around 950 mg. Among nuts specifically, mean total phytosterol content ranged from 71.7 mg (Brazil nuts) to 271.9 mg (pistachios) per 100 g oil, with β-sitosterol being the major sterol, followed by minor contents of campesterol, ergosterol, and stigmasterol.

Phytosterol intake in modern populations is substantially lower than in ancestral diets. Unlike the typical diet in most developed countries today, the diets of our ancestors were rich in phytosterols, likely providing as much as 1 g/day. Present-day dietary phytosterol intakes have been estimated to vary from 150 to 450 mg/day in different populations. Vegetarians, particularly vegans, generally have the highest intakes of dietary phytosterols. The typical western diet contains only about 300 mg/day of phytosterols, so foods enriched with phytosterols are usually used to achieve recommended intakes.

Because of the difficulty in reaching therapeutic doses through unfortified foods, manufacturers add concentrated plant sterols to products like margarine spreads, orange juice, yogurt, and breakfast cereals. Since the first Novel Foods authorisation for the use of plant sterol-esters in yellow fat spreads, other authorisations have taken place for the use of plant sterol-esters in a variety of food formats.

3. Traditional and Historical Use

Throughout much of human evolution, it is likely that large amounts of plant foods were consumed. In addition to being rich in fiber and plant protein, the diets of our ancestors were also rich in phytosterols — plant-derived compounds that are structurally very similar to cholesterol. While phytosterols themselves were not isolated or identified as a distinct chemical class in pre-modern times, they were consumed in substantial amounts as intrinsic constituents of plant-based diets across all cultures. Traditionally, plant-based products have been used for different purposes; from ancient times, people on all continents have long applied poultices and imbibed infusions of indigenous plants.

The formal history of phytosterols as identified, intentionally used compounds is more recent. Phytosterols have a long history of safe use, dating back to Cytellin, the pharmaceutical preparation of phytosterols marketed in the US from 1954 to 1982. In the domain of botanical medicine, the phytosterol β-sitosterol has historically been used within phytotherapeutic preparations for urological complaints. The pharmacologic use of plants and herbs for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) has been growing steadily. Phytotherapeutic preparations containing beta-sitosterols, derived from the South African star grass, Hypoxis rooperi, or from species of Pinus and Picea, are available for the treatment of BPH. These plant sources were used traditionally in southern African and European folk medicine before their phytosterol content was characterized analytically.

In the context of food science and functional nutrition, phytosterol-enriched functional foods first appeared about twenty years ago, and many clinical studies have confirmed the LDL cholesterol-lowering properties of various types of phytosterols.

4. Key Constituents and Active Compounds

The phytosterol class encompasses a large number of individual molecules, of which a small group accounts for the majority of biological activity in human nutrition:

• β-Sitosterol: β-sitosterol is a major bioactive constituent and the most abundant phytosterol in nuts, seeds, and vegetable oils; it is structurally similar to cholesterol, except for the addition of the ethyl group.
• Campesterol: The second most abundant phytosterol in the diet; structurally it differs from cholesterol only by an additional methyl group at C-24. Corn oil and rice bran oil have higher contents of campesterol and total phytosterol and may be better choices for patients with high cholesterol and cardiovascular diseases.
• Stigmasterol: Stigmasterol, alongside campesterol and beta-sitosterol in plants, is a primary component of cellular and sub-cellular membranes in plant cell types.
• Plant stanols (phytostanols): The fully saturated counterparts of phytosterols. Phytostanols are saturated sterol alcohols present in only trace amounts in nature and may also be synthetically produced by hydrogenation of phytosterols. Commercially, sitostanol (used in products such as Benecol) is produced industrially by hydrogenation of sitosterol.

Within plant physiology, phytosterols perform essential structural and signaling roles. Phytosterol glucosides have been found to be important structural components in the lipid rafts of the plasma membrane of plant cells, where they are thought to be essential to the function of plasma membrane enzymes and perhaps other proteins. Phytosterols also serve as precursors in the synthesis of important bioactive compounds such as steroidal saponins, steroidal glycoalkaloids, phytoecdysteroids, and brassinosteroids.

5. Mechanisms of Action

5.1 Cholesterol Absorption Inhibition

The primary and best-established mechanism of phytosterols in human health is the competitive inhibition of intestinal cholesterol absorption. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Phytosterols displace cholesterol from intestinal micelles, reducing the pool of absorbable cholesterol, but they are also rapidly taken up by enterocytes and increase expression of the adenosine triphosphate-binding cassette A1 sterol transporter. This dual mechanism — competitive micellar displacement plus active efflux back into the intestinal lumen — accounts for the net reduction in cholesterol absorption observed in clinical studies.

A secondary hepatic mechanism also contributes to LDL lowering: phytosterols reduce cholesterol absorption and synthesis, thereby prompting an upsurge in endogenous cholesterol production and augmenting the hepatic uptake of plasma LDL-C, enhancing its clearance and lowering plasma concentration.

The NPC1L1 transporter pathway is specifically implicated in phytosterol action. Plant sterols/stanols can reduce cholesterol absorption at the intestinal lumen through the Niemann-Pick C1 Like 1 (NPC1L1) transporter pathway by competitive solubilization in mixed micelles. Phytosterol absorption is of less magnitude than cholesterol and is preferably secreted in the intestinal lumen by ABCG5/G8 transporters. Therefore, plasma levels of plant sterols/stanols are negligible compared with cholesterol, under an ordinary diet.

5.2 Triglyceride Metabolism

Phytosterols lower liver TG production by blocking fat-making enzymes and help break down TG by boosting an enzyme called lipoprotein lipase.

5.3 Anti-Inflammatory and Antioxidant Properties

Phytosterols possess various bioactive properties, including antioxidant, anti-inflammatory, chemopreventive, cholesterol-lowering, and neuroprotective effects. At the molecular level, phytosterols prevent cancer development by scavenging reactive oxidative species (ROS) and boosting antioxidant enzymes, thus inhibiting DNA damage and cell mutations; they also regulate important signal transduction processes such as NF-κB, PI3K/Akt, and MAPK/ERK that drive cell growth, survival, and metastasis. These mechanisms have been characterized largely in preclinical (in vitro and animal) models.

5.4 Anticancer Mechanisms (Preclinical)

Phytosterols induce apoptosis, block the cell cycle, and abrogate the invasion and metastasis of cancer cells. Potential biological mechanisms that may account for cancer-related associations include promoting apoptosis, arresting the cell cycle, and reducing the production of reactive oxygen species (ROS), all of which have been experimentally verified.

5.5 Anti-Diabetic Mechanisms (Preclinical)

Phytosterols have been shown to have multiple therapeutic implications, including hypolipidemic, anti-inflammatory, antioxidant, antiproliferative, and hypoglycemic potential through experimental evidence. β-sitosterol is a strong neuroprotective, chemoprotective, and anti-diabetic natural sterol that increases the generation of total antioxidants in cells. These mechanisms are based predominantly on animal and cell-based studies; their translation to human clinical outcomes remains to be fully established.

6. Scientific Evidence by Area of Use

6.1 Cardiovascular Health: LDL Cholesterol Reduction

This is the most extensively studied and robustly supported application of phytosterols in human health. The evidence base includes dozens of randomized controlled trials (RCTs) and multiple systematic reviews and meta-analyses.

Clinical studies consistently indicate that the intake of phytosterols at 2 g/day is associated with a significant reduction (8–10%) in levels of LDL-cholesterol. Several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels.

A comprehensive review of the evidence across diverse populations and interventions confirmed: irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia, and even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%–10%. They do not affect the concentrations of HDL-cholesterol, lipoprotein(a), or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels, especially in subjects with slightly increased baseline concentrations.

A 2025 systematic review and meta-analysis of 14 RCTs in 1,088 hyperlipidemic participants showed: the pooled results demonstrated statistically significant reductions in total cholesterol (TC) levels (mean difference = −0.65, 95% CI −0.83 to −0.47, P < 0.00001) and LDL-C levels (MD = −0.52, 95% CI −0.66 to −0.38, P < 0.00001), along with a modest increase in HDL-C levels. However, the same meta-analysis failed to demonstrate anti-inflammatory activity as measured by CRP levels. The observed marginal TG-lowering effect should be interpreted with caution given substantial interstudy heterogeneity.

A controlled feeding study examined dose-response relationships: the study was a highly controlled feeding trial in which participants consumed phytosterol-deficient diets plus supplemental beverages providing 0, 400, or 2000 mg phytosterols/day. The researchers found that both moderate and high intakes of phytosterols significantly increased fecal cholesterol excretion, with the higher dose eliciting a greater effect. In addition, high phytosterol intake significantly reduced LDL cholesterol levels, and a nonsignificant trend was observed for moderate intake. Although supplemental sources of plant sterols produce the greatest effect, even moderate phytosterol intake — such as that obtained from a diet rich in plant-based foods — provides cholesterol-lowering effects in humans.

Evidence also demonstrates meaningful effects from naturally occurring phytosterols in whole foods: in single-meal tests, removal of 150 mg of phytosterols from corn oil increased cholesterol absorption by 38%, and removal of 328 mg of phytosterols from wheat germ increased cholesterol absorption by 43%.

Phytosterol esters dissolved in food fat reduce LDL-cholesterol by 10% at a maximum effective dose of 2 g/day. The dose-response relationship shows diminishing returns beyond this level; based on a meta-analysis of 124 studies, intakes of 0.6 to 1.1 grams per day achieve at least a 5% reduction in LDL cholesterol. Going above 3 grams does not produce proportionally larger benefits.

Regulatory position: EFSA experts have concluded that foods such as yoghurt and margarine containing certain levels of plant stanols and sterols can reduce blood cholesterol levels, and this advice guides the European Commission and Member States in the authorisation of such health claims. In 2009 the European Commission authorised a health claim of disease risk reduction due to the LDL-cholesterol lowering effect of phytosterols based on positive opinions by EFSA. In the United States, it has been recognized for many years that phytosterols reduce total and LDL cholesterol levels in humans, which is why the National Cholesterol Education Program recommends adults consume 2 grams of phytosterols daily to help protect against cardiovascular disease.

The European Atherosclerosis Society has defined specific populations for phytosterol use: based on the reducing effect on LDL-cholesterol and absence of adverse signs, the consumption of foods enriched with phytosterols may be considered: (1) in individuals with hypercholesterolemia presenting intermediate or low cardiovascular risk without indication of pharmacotherapy; (2) as an adjunct to pharmacological therapy in patients with high and very high cardiovascular risk who fail to achieve LDL-cholesterol goals with statins or are intolerant to statins; and (3) in adults and children (>6 years) with familial hypercholesterolemia, along with lifestyle changes and drug therapy.

6.2 Cardiovascular Disease Events: An Important Limitation

Despite the well-established LDL-lowering effect, the translation to reduced cardiovascular events remains unproven and is a subject of active debate. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. The intake of phytosterols (83 to 966 mg/day) from natural sources was not found to be associated with reduced risks of coronary heart disease (CHD), myocardial infarction, or total cardiovascular disease during the 12.2-year follow-up of 35,597 participants of the European Prospective Investigation. Observational studies show no evidence that plasma phytosterol concentrations would be associated with an increased risk of atherosclerosis or cardiovascular events. The ongoing debate is partly informed by findings in patients with phytosterolemia (see Safety section), and the question of whether mildly elevated plasma phytosterol levels — which can occur with supplementation — carry independent atherogenic risk remains unresolved.

6.3 Phytosterols as Adjunctive Therapy with Statins

A meta-analysis of 15 randomized controlled trials investigating the effects of phytosterol-enriched food intake (1.8 to 6 g/day of phytosterols) in patients treated with statins found that co-administration of phytosterols and statins significantly reduced total cholesterol and LDL-cholesterol concentrations compared to statin therapy alone. The concentrations of HDL-cholesterol and triglycerides were unaffected by the combination of phytosterols and statins compared to statin alone. In subgroup analyses, the effect of combining phytosterols and statins on blood lipid profile was not found to be significantly influenced by lipid baseline values, phytosterol dosage, or study duration. The additive effect of phytosterols is mechanistically logical because statins act at the level of endogenous cholesterol synthesis (inhibiting HMG-CoA reductase), while phytosterols act at intestinal absorption — two complementary pathways.

6.4 Benign Prostatic Hyperplasia (BPH)

The use of β-sitosterol for BPH has been evaluated in a Cochrane systematic review. This systematic review aimed to assess the effects of beta-sitosterols on urinary symptoms and flow measures in men with benign prostatic hyperplasia. β-Sitosterols improved urinary symptom scores and flow measures. The weighted mean difference (WMD) for the IPSS was −4.9 IPSS points (95% CI = −6.3 to −3.5, n = 2 studies). The WMD for peak urine flow was 3.91 ml/sec (95% CI = 0.91 to 6.90, n = 4 studies) and the WMD for residual volume was −28.62 ml (95% CI = −41.42 to −15.83, n = 4 studies).

β-Sitosterols did not reduce prostate size. The evidence suggests non-glucosidic β-sitosterols improve urinary symptoms and flow measures. Their long-term effectiveness, safety, and ability to prevent BPH complications are not known.

A 2025 mechanistic study lent further support: the natural phytosterol β-sitosterol effectively inhibits both prostate contraction and growth with a favorable safety profile, supporting its beneficial role in LUTS management through phytotherapy. The overall evidence for BPH is considered promising but limited by the short duration of trials and the absence of long-term follow-up data.

6.5 Cancer: Epidemiological and Preliminary Evidence

Phytosterols have multifactorial modes of action such as antioxidant, anti-inflammatory, and apoptotic, which render them potentially useful in the prevention and treatment of prostate, breast, colon, bladder, and skin cancer. Several epidemiological studies have indicated that phytosterol intake is related to the lower risk of stomach, colorectal, esophageal, breast, and lung cancer.

One clinical dataset showed: among 1,802 cancer patients studied, those with a high dietary intake of phytosterols demonstrated a significantly reduced risk of developing colon cancer compared to individuals with lower intake levels. Specifically, participants in the highest quartile of phytosterol consumption experienced a 50% reduction in the risk of colon cancer compared to those in the lowest quartile. This finding is epidemiological and cannot establish causation.

Clinical use of phytosterols for cancer is limited due to factors like low bioavailability, which researchers are attempting to overcome with nanotechnology and drug delivery approaches. Based on preclinical and epidemiological studies, phytosterols can be considered a useful adjunctive component to cancer treatments, but more studies are required to work out clinical testing and streamlined delivery to maximize effectiveness in cancer treatment. There are considerable research gaps because there are almost no clinical studies to examine the safety and effectiveness of β-sitosterol for various human diseases.

6.6 Metabolic Syndrome and Type 2 Diabetes

A systematic review aimed to evaluate the effects of phytosterol supplementation on metabolic syndrome components in RCTs. Phytosterols, as plant-like organic structures with close similarity to cholesterol, might be therapeutically useful for hypertension, central obesity, dyslipidemia, and hyperglycemia, which are components of metabolic syndrome.

Phytosterols have been studied extensively for the treatment and management of diabetes, a variety of malignancies, cardiovascular disorders, atherosclerosis, and skin problems, and have shown multiple therapeutic implications including hypolipidemic, anti-inflammatory, antioxidant, antiproliferative, and hypoglycemic potential through experimental evidence. A rising number of anti-diabetic studies have demonstrated phytosterols to be helpful in vivo and in vitro; however, a comprehensive study of the preventative and prospective mechanisms of food-derived phytosterols for diabetes and its consequences has yet to be identified. The evidence base for anti-diabetic effects of phytosterols in humans remains preliminary.

6.7 Inflammatory Markers

Despite preliminary mechanistic data suggesting anti-inflammatory properties, clinical evidence for phytosterols reducing systemic inflammation is inconsistent. The 2025 systematic review and meta-analysis of phytosterol-rich foods in hyperlipidemic patients found that phytosterol intervention demonstrates significant efficacy in modulating atherogenic lipid profiles such as TC and LDL-C, while also elevating HDL-C levels, yet fails to demonstrate anti-inflammatory activity as measured by CRP levels. Larger, metabolomics-inclusive studies are required for definitive conclusions and clinical guidance.

7. Dosage Forms and Reported Dosages

Phytosterols are delivered in several forms, each with different bioavailability considerations:

• Phytosterol esters in fat-containing foods: The most clinically studied format. Clinical trials that demonstrated a cholesterol-lowering effect have primarily used plant sterol or stanol esters solubilized in fat-containing foods, such as margarine or mayonnaise.
• Fortified non-fat foods and beverages: Phytosterols can be emulsified with lecithin and delivered in non-fat or low-fat foods and beverages, though fewer clinical trials have examined these formats.
• Dietary supplements (capsules/tablets): Available as free phytosterols or phytosterol esters; used in the BPH evidence base and in lipid management studies.

Doses used in studies and recommended by guidelines:

• Clinical studies consistently indicate that the intake of phytosterols at 2 g/day is associated with a significant reduction (8–10%) in LDL-cholesterol levels.
• Phytosterol esters dissolved in food fat reduce LDL-cholesterol by 10% at a maximum effective dose of 2 g/day.
• Single meal studies show that phytosterols in intact foods are bioactive at doses as low as 150 mg.
• The meta-analysis of co-administration with statins used phytosterol-enriched food intake of 1.8 to 6 g/day.
• For BPH, the Cochrane review used preparations of β-sitosterol in RCTs with treatment durations of at least 30 days; doses in included trials were in the range used in typical phytotherapy products for BPH.
• The dose-response meta-analysis (124 studies) indicated: intakes of 0.6 to 1.1 grams per day achieve at least a 5% reduction in LDL cholesterol, and going above 3 grams does not produce proportionally larger benefits.
• For the metabolic syndrome systematic review, one double-blind, placebo-controlled, crossover study administered 1.6 g/day of phytosterols (in soy milk) for 4 weeks to 38 moderately hypercholesterolemic volunteers.

8. Body Systems and Health Areas

Phytosterols possess various bioactive properties, including antioxidant, anti-inflammatory, chemopreventive, cholesterol-lowering, and neuroprotective effects. Through these mechanisms, dietary phytosterols may help prevent cardiovascular and neurodegenerative diseases, type 2 diabetes, and certain cancers. The body systems most clearly associated with phytosterol activity, ranked by strength of clinical evidence, include:

• Cardiovascular system / lipid metabolism: Strongest evidence; well-replicated RCTs and meta-analyses confirm LDL-C reduction of 8–10% at 2 g/day. The impact on actual cardiovascular events is not established.
• Urogenital system (prostate): Moderate evidence from a Cochrane review supporting improvement of BPH urinary symptoms and flow measures with β-sitosterol; prostate size is not reduced.
• Immune / inflammatory system: Preclinical evidence of NF-κB modulation, antioxidant activity, and anti-inflammatory actions. Clinical evidence of CRP reduction is currently negative.
• Oncological (cancer prevention): Epidemiological associations and preclinical mechanism data; no confirmed clinical evidence from interventional trials.
• Metabolic / endocrine system (glucose metabolism): Preclinical (in vivo and in vitro) evidence of hypoglycemic and insulin-sensitizing effects; clinical evidence is preliminary.
• Gastrointestinal system: Central to mechanism of action — phytosterols act in the small intestine to reduce cholesterol micellar solubilization and absorption.

9. Safety Considerations and Interactions

9.1 General Safety Status

Phytosterols have a long history of safe use, dating back to Cytellin, the pharmaceutical preparation of phytosterols marketed in the US from 1954 to 1982. Phytosterol esters have generally recognized as safe (GRAS) status in the US. Phytosterol-containing functional foods were subject to post-launch monitoring after being introduced to the EU market in 2000, and no unpredicted side effects were reported.

9.2 Carotenoid and Fat-Soluble Vitamin Reduction

Considering that phytosterols reduce the intestinal absorption of cholesterol, it is reasonable to imagine that these substances may also reduce the absorption of liposoluble vitamins and antioxidants. The serum levels of vitamins A, D, and K1 are generally not affected by the consumption of phytosterols. However, some studies suggest that phytosterols may promote a modest reduction in plasma concentration of carotenoids (mainly β-carotene, α-carotene, and lycopene) and tocopherols, but other studies have not observed this.

A meta-analysis examined this effect: it included 41 randomized clinical trials (n = 3,306) with a mean phytosterol intake of 2.5 g/day. A practical mitigation strategy exists: it is possible to avoid reductions in plasma carotenoid concentrations during the consumption of phytosterols through an increase in daily consumption of carotenoid-rich fruits and vegetables. Consumption of phytosterol-enriched foods may have undesirable effects, such as a reduction in plasma carotenoid concentrations.

9.3 Phytosterolaemia (Sitosterolaemia)

A potential safety concern regarding phytosterol consumption is in patients with phytosterolaemia, a rare genetic disorder which results in a 50- to 100-fold increase in blood plant sterol levels and is associated with rapid development of coronary atherosclerosis. This condition is caused by homozygous defects in the genes encoding the ABCG5/G8 tandem transporter, which modulates the absorption of about forty sterols, including cholesterol and non-cholesterol sterols, with various complex effects on sterol and lipid metabolism and other tissue and organ functions. Phytosterolaemia is a contraindication to the use of phytosterol-containing functional foods and supplements.

9.4 Pregnancy, Lactation, and Children

Although the health effects of chronically low blood carotenoid concentrations are largely unknown, there could be cause for concern during developmental phases when requirements are higher than normal, such as during pregnancy, lactation, or infancy. In addition, cholesterol-lowering is typically not a priority for these groups.

9.5 Interactions with Statins

There is controversy about treatment with statins inducing further increase in plasma non-cholesterol sterols, raising concerns about the safety of supplementation of plant sterols to such drugs. Studies showed that with more potent statins, the reduction in markers of endogenous synthesis was followed by elevation in plasma plant sterol levels, proportional to the statin potency. However, the clinical significance of these elevated plasma phytosterol levels in the context of statin co-administration has not been definitively resolved. From an efficacy standpoint, plant stanols have an additive LDL-C-lowering effect when associated with ongoing statin therapy. These observations make plant stanols and sterols attractive dietary components to help in achieving LDL-C goals in patients requiring a lipid-lowering drug.

9.6 Potential Atherogenicity of Elevated Plasma Phytosterols

Phytosterols have been proposed as dietary means to lower plasma LDL-C; however, concerns are raised that they may exert atherogenic effects, which would offset this benefit. A number of studies have suggested that high serum plant sterol values may be associated with increased risk of coronary heart disease. Nevertheless, observational studies show no evidence that plasma phytosterol concentrations would be associated with an increased risk of atherosclerosis or cardiovascular events in the general population. This remains an area of active scientific discussion. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols.

9.7 Bioavailability Limitations

Limited water solubility, absorption, bioavailability, crystallization at room temperature and body temperature, and high required daily doses (up to 3 g/day) are the major issues related to the oral supplementation of β-sitosterol. These issues mainly limit β-sitosterol production and the progress of clinical trials. Clinical use of phytosterols is limited due to factors like low bioavailability, which researchers are attempting to overcome with nanotechnology and drug delivery approaches.

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