Scientific Name(s): Βeta-sitosterol
Common Name(s): Phytosterol, Plant sterol
Dietary consumption is the main source of plasma phytosterols, which are not synthesized endogenously. Fortified margarines used for lowering cholesterol contain 2 g of plant sterols per daily portion.1 The sitosterols are usually obtained from soybean oil,2 peanut oil (207 mg per 100 g of unrefined oil),3 and avocado oil (76 mg per 100 g).4 Preparations containing beta-sitosterol derived from the South African star grass Hypoxis rooperi or from species of Pinus and Picea are available for the treatment of BPH.5 Saw palmetto berries also contain large quantities of beta-sitosterol and other plant sterols.
Plant sterols were chemically described in 1922.6 In the 1950s, it was noted that these sterols lower serum cholesterol concentrations by reducing the absorption of cholesterol from the gut. However, by the 1980s, statins were introduced to the market, and the role of plant sterols in lipid lowering was diminished. Subsequently, it has been recognized that, as naturally occurring substances, plant sterols can be added to foods. Margarine appears to be an ideal vehicle, although cream cheese, salad dressing, and yogurt are also used.1 Over the last 15 years, there also have been several reports in the literature indicating that phytosterols have some immunological activity.6
Sterols are essential components of cell membranes, and both animals and plants produce them. The sterol ring system is common to all sterols; the differences are in the side chain. Phytosterols are 28- or 29-carbon alcohols.7 Beta-sitosterol is the most common plant sterol and is structurally similar to cholesterol.1 Because of this structural similarity, beta-sitosterol can replace cholesterol in the human body.2 Beta-sitosterol is a 4-desmethyl sterol (lacking a methyl group at carbon atom number 4).1, 2 It has a double bond at the C-5 position in the ring,8 and it is usually esterified with fatty acids for incorporation into margarine.2
Uses and Pharmacology
Cholesterol-lowering effects and other cardiovascular effects
Plant sterols in fortified margarine reduce the absorption of cholesterol from the gut by about half. This reduced absorption lowers serum cholesterol concentrations despite the compensatory increase in cholesterol synthesis that occurs in the liver and other tissues. Plant sterols are potentially atherogenic, like cholesterol, but atherogenesis does not occur because very little of the plant sterol is absorbed (approximately 5% of beta-sitosterol).1
Animal/In vitro data
In tumor necrosis factor (TNF)-alpha–stimulated human aortic endothelial cells, beta-sitosterol was found to significantly inhibit vascular adhesion molecule 1 and intracellular adhesion molecule 1 expression. A potential cardioprotective effect was also suggested.9
A meta-analysis of 14 randomized controlled trials (N = 473) investigated the effects of plant sterols and stanols (when added to margarine) on cholesterol. LDL cholesterol ranged from 116 to 174 mg/dL in the control groups in these studies, consistent with normal values in the general population. The fortified margarine reduced the mean concentration of LDL cholesterol, and the effect increased with age. In each age group, the dose response relation was linear up to a dosage of about 2 g/day of plant sterol or stanol. At doses of 2 g or higher, the average reduction in LDL cholesterol was 21 mg/dL for participants 50 to 59 years of age, 17 mg/dL for participants 40 to 49 years of age, and 13 mg/dL for those 30 to 39 years of age. At higher doses, no further reduction in LDL cholesterol was apparent. This trend was statistically significant (P = 0.005).1
Data suggest that in people 50 to 59 years of age, a reduction in LDL cholesterol concentration of 20 mg/dL would reduce the risk of heart disease by approximately 25% after 2 years. The effect is calculated to be superior to that expected if people merely ate less animal fat. For a person replacing butter with a plant sterol margarine, the reduction in cholesterol would be even greater.1
In a parallel, double-blind study, 164 Finnish patients with hypercholesterolemia were randomized to receive plant sterols targeted at 2 g/day or placebo for 6 weeks. Treatment resulted in a 6.5% decrease in total cholesterol and a 10.4% decrease in LDL cholesterol in those receiving plant sterols (P < 0.0005, P < 0.00005, respectively). High-density lipoprotein cholesterol levels did not change.10 In a randomized, double-blind, placebo-controlled trial, the addition of phytosterol to red yeast rice therapy and life style changes did not result in any further reductions in lipid parameters compared with placebo.33
As a component of medical nutrition therapy for patients with type 1 or type 2 diabetes, the American Diabetes Association Standards of Care (2014) recommends an increase in foods containing n-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; from fatty fish), viscous fiber (eg, oats, legumes, citrus), and plant-based stanols or sterols to help treat dyslipidemias in most diabetic patients (ie, those who do not have severe hypertriglyceridemia) (high quality evidence).34
Beta-sitosterol increased the proliferation of peripheral blood lymphocytes and enhanced the cytotoxic effect of natural killer cells. Further investigation revealed anti-inflammatory properties and has led to suggestions of a role in the control of chronic inflammatory conditions.6
Excessive physical stress, such as that observed in marathon runners, can cause subtle immunosuppression. This may be due in part to the disruption of normal physiological equilibrium or homeostasis, including that of the immune system. Administration of beta-sitosterol prevented the typical neutrophilia, lymphopenia, and total leukocytosis that occurs in times of excessive physical stress.11
Animal/In vitro data
In a study of peripheral blood mononuclear cells from patients with multiple sclerosis, beta-sitosterol reduced TNF-alpha release by 24% and reduced interleukin (IL)-12 release by 27% to 30%, depending on concentration. Anti-inflammatory cytokine IL-10 release was increased by 47% with beta-sitosterol administration in healthy subjects.12
A randomized controlled trial of 47 patients with pulmonary tuberculosis investigated adjuvant beta-sitosterol therapy versus placebo. The beta-sitosterol treatment group (average dosage of 60 mg/day) demonstrated increased weight gain, higher lymphocyte and eosinophil counts, and a generally faster clinical recovery.13
Animal/In vitro data
Beta-sitosterol has demonstrated effects on tumor cell lines in vitro. Growth is inhibited in human colon, stomach, prostate, and breast cancer cell lines as well as in multiple myeloma. It has been postulated that cell death (apoptosis) is initiated, probably by activation of the protein phosphatase A2 pathway.14, 15, 16, 17, 18, 19 Studies using rat and mice models have shown beta-sitosterol to reduce the number of tumors.6
In PC-3 cells, the combination of beta-sitosterol and resveratrol was believed to be synergistic against prostate cancer through apoptosis and by arresting cell growth at various states in the cell cycle to ultimately suppress tumor growth.18 Another study showed that beta-sitosterol inhibited growth in DU-145 prostate cancer cells through increased p53 protein expression and decreased p21 and p27 protein expression.19
Beta-sitosterol inhibited cell growth of MCF-7 (estrogen receptor–positive) and MDA-MB-231 (estrogen receptor–negative) breast cancer cell lines. Additionally, a combination of beta-sitosterol and tamoxifen was found to inhibit breast cancer cell growth.20
A cohort study performed in the Netherlands found that plant sterols had no effect on the risk of colon and rectal cancers. For 6.3 years, 120,852 patients 55 to 69 years of age were followed, with an average consumption of 285 mg plant sterols per day.8
Benign prostatic hyperplasia
This nonmalignant enlargement of the prostate can lead to obstructive and irritative lower urinary tract symptoms. The majority of men over 60 years of age are considered to have urinary symptoms attributable to BPH. The pharmacological use of plants and herbs for the treatment of BPH symptoms has been steadily growing in most countries. Nearly a quarter of men seen with previously treated BPH at a university urology clinic for urinary symptoms indicated that they had tried phytotherapeutic agents.5
Beta-sitosterol may have a potential role in inhibiting 5-alpha-reductase as well as reducing steroid hormone biosynthesis, thereby reducing testosterone levels.21
In gonadectomized hamster prostates, beta-sitosterol was found to inhibit the 5-alpha-reductase enzyme following subcutaneous administration.22
A Cochrane review of 4 randomized, controlled trials comparing beta-sitosterol with placebo (or other BPH medications) investigated the effects of beta-sitosterol on the outcomes of urinary symptom scores and flow measures. The treatment duration was short, with no study lasting longer than 26 weeks, and fewer than 600 men were evaluated. Beta-sitosterol improved urinary symptoms and flow measures and was generally well tolerated. The authors of this review suggested that beta-sitosterol may be a useful treatment option for men with mild to moderate BPH, particularly in those who would like to avoid or are at increased risk for adverse effects from alpha-adrenergic receptor blockers.5 These agents (eg, prazosin) selectively block alpha-1-adrenergic receptors. The degree of smooth muscle tone in the prostate and bladder neck is mediated by the alpha-1-adrenergic receptor, which is present in high density in the prostatic stroma, prostatic capsule, and bladder neck. Blockade of the alpha-1-adrenergic receptor decreases urethral resistance and may relieve the obstruction and improve urine flow and BPH symptoms.
Beta-sitosterol may be useful in patients with androgenic alopecia because of its ability to reduce testosterone through inhibition of steroid hormone biosynthesis.21
There are no animal data regarding the use of beta-sitosterol for androgenic alopecia.
In a study of 19 men between 23 and 64 years of age with mild to moderate androgenic alopecia, 60% of participants stated an "improvement" had occurred from baseline (approximately 5 months of treatment) after taking a treatment containing 50 mg of beta-sitosterol and 200 mg of saw palmetto extract compared with 11% of participants who had received placebo. This suggests a possible role for beta-sitosterol in patients with androgenic alopecia.21
Animal/In vitro data
Beta-sitosterol, along with various other compounds isolated from Ageratina pichinchensis var. bustamenta, was found to exert antimicrobial affects against Trichophyton species, which can cause tinea pedis infections.23 Another in vivo study showed that beta-sitosterol derived from Ginkgo biloba leaves exerted antibacterial effects against Salmonella enterica and Staphylococcus aureus.24
There are no clinical data regarding the use of beta-sitosterol for its antimicrobial effects.
Beta-sitosterol is incorporated in margarine, yogurt, or other foods to provide a daily intake of 1.5 to 3 g.
Pregnancy / Lactation
Beta-sitosterol should be avoided in pregnant women due to demonstrated uterine stimulant effects. In a study of rats, beta-sitosterol derived from pomegranate seeds increased spontaneous uterine contractions in a concentration-dependent fashion through effects on calcium-activated K channels. Specifically, it increased uterine contraction force and duration, but not frequency. Maximum effects were noted at 1 mg per 100 mL.25
Plant sterols reduce the absorption of the fat-soluble vitamins beta-carotene, alpha-carotene, and vitamin E. No effects on vitamins A and K have been noted.1 Beta-sitosterol levels may decrease in patients receiving ezetimibe through its inhibition of intestinal absorption of plant sterols.26
On the basis of extensive safety evaluation studies, the plant sterols are generally recognized as safe (GRAS) when consumed in margarine at the recommended doses. However, a review of the literature suggests that beta-sitosterol may cause GI adverse effects as well as impotence.27 In 1 study, adverse reactions deemed related to beta-sitosterol use were flatulence, discoloration of the feces, appetite changes, dyspepsia, leg cramps, skin rash, and leukopenia.7 In rats, a decrease in testicular weight and sperm concentration occurred with prolonged treatment at a low dose (0.5 mg/kg) of beta-sitosterol. Antifertility effects were noted at a higher dose (5 mg/kg).7 In a study of rats, administration of a phytosterol diet for 5 weeks resulted in increases in systolic and diastolic blood pressure values.28, 29 A 1-year study in healthy patients consuming 1.6 g/day of plant sterols contained in a dietary spread demonstrated cholesterol-lowering effects as well as general tolerability with long-term consumption.30 Increased concentrations of phytosterols in erythrocyte membranes may result in increased fragility; episodes of hemolysis have been reported, but these adverse reactions occurred in patients with sitosterolemia.31 Despite no evidence of harm with beta-sitosterol use, hydrogenation into transfatty acids does occur with margarine ingestion. Therefore, margarine cannot be recommended as the sole therapeutic option in the diseases mentioned in this monograph.
In a study of hamsters, diets containing oxidation products of phytosterols (ie, beta-sitosterol, stigmasterol) resulted in greater liver weights compared with controls. Additionally, hamsters receiving the oxidation products lost the capacity to lower total cholesterol, LDL, and triacylglycerols.29, 32
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