Vitamin E

Vitamin E is a group of eight

Vitamin E was discovered in 1922, isolated in 1935, and first synthesized in 1938. Because the vitamin activity was first identified as essential for fertilized eggs to result in live births (in rats), it was given the name "tocopherol" from Greek words meaning birth and to bear or carry. Alpha-tocopherol, either naturally extracted from plant oils or, most commonly, as the synthetic tocopheryl acetate, is sold as a popular dietary supplement, either by itself or incorporated into a multivitamin product, and in oils or lotions for use on skin.

Chemistry

The nutritional content of vitamin E is defined by equivalency to 100% RRR-configuration α-tocopherol activity. The molecules that contribute α-tocopherol activity are four tocopherols and four tocotrienols, within each group of four identified by the prefixes alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-). For alpha(α)-tocopherol each of the three "R" sites has a methyl group (CH₃) attached. For beta(β)-tocopherol: R1 = methyl group, R2 = H, R3 = methyl group. For gamma(γ)-tocopherol: R1 = H, R2 = methyl group, R3 = methyl group. For delta(δ)-tocopherol: R1 = H, R2 = H, R3 = methyl group. The same configurations exist for the tocotrienols, except that the hydrophobic side chain has three carbon-carbon double bonds whereas the tocopherols have a saturated side chain.^[11]

Stereoisomers

In addition to distinguishing tocopherols and tocotrienols by position of methyl groups, the tocopherols have a phytyl tail with three

Form	Structure
alpha-Tocopherol
beta-Tocopherol
gamma-Tocopherol
delta-Tocopherol
Tocopheryl acetate

Tocopherols

The four tocotrienols (alpha, beta, gamma, delta) are similar in structure to the four tocopherols, with the main difference being that the former have hydrophobic side chains with three carbon-carbon double bonds, whereas the tocopherols have saturated side chains. For alpha(α)-tocotrienol each of the three "R" sites has a methyl group (CH₃) attached. For beta(β)-tocotrienol: R1 = methyl group, R2 = H, R3 = methyl group. For gamma(γ)-tocotrienol: R1 = H, R2 = methyl group, R3 = methyl group. For delta(δ)-tocotrienol: R1 = H, R2 = H, R3 = methyl group. Palm oil is a good source of alpha and gamma tocotrienols.^[15]

Tocotrienols have only a single

Vitamin E may have various roles as a

Vitamin E affects gene expression^[22] and is an enzyme activity regulator, such as for protein kinase C (PKC) – which plays a role in smooth muscle growth – with vitamin E participating in deactivation of PKC to inhibit smooth muscle growth.^[23]

Synthesis

Biosynthesis

Photosynthesizing plants,

As to why plants synthesize tocochromanols, the major reason appears to be for antioxidant activity. Different parts of plants, and different species, are dominated by different tocochromanols. The predominant form in leaves, and hence leafy green vegetables, is α-tocopherol.[24] Location is in chloroplast membranes, in close proximity to the photosynthetic process.^[25] The function is to protect against damage from the ultraviolet radiation of sunlight. Under normal growing conditions the presence of α-tocopherol does not appear to be essential, as there are other photo-protective compounds, and plants that through mutations have lost the ability to synthesize α-tocopherol demonstrate normal growth. However, under stressed growing conditions such as drought, elevated temperature or salt-induced oxidative stress, the plants' physiological status is superior if it has the normal synthesis capacity.^[26]

Seeds are lipid-rich, to provide energy for germination and early growth. Tocochromanols protect the seed lipids from oxidizing and becoming rancid.^[24][25] The presence of tocochromanols extends seed longevity, and promotes successful germination and seedling growth.^[26] Gamma-tocopherol dominates in seeds of most plant species, but there are exceptions. For canola, corn and soy bean oils, there is more γ-tocopherol than α-tocopherol, but for safflower, sunflower and olive oils the reverse is true.^[24][25][15] Of the commonly used food oils, palm oil is unique in that tocotrienol content is higher than tocopherol content.^[15] Seed tocochromanols content is also dependent on environmental stressors. In almonds, for example, drought or elevated temperature increase α-tocopherol and γ-tocopherol content of the nuts. The same article mentions that drought increases the tocopherol content of olives, and heat likewise for soybeans.^[27]

Vitamin E biosynthesis occurs in the plastid and goes through two different pathways: the Shikimate pathway and the Methylerythritol Phosphate pathway (MEP pathway).^[24] The Shikimate pathway generates the chromanol ring from the Homogentisic Acid (HGA) and the MEP pathway produces the hydrophobic tail which differs between tocopherol and tocotrienol. The synthesis of the specific tail is dependent on which molecule it originates from. In a tocopherol, its prenyl tail emerges from the geranylgeranyl diphosphate (GGDP) group, while the phytyl tail of a tocotrienol stems from a phytyl diphosphate.^[24]

Focusing on tocopherols, the synthesis of its derivatives stems from the reaction between the HGA and the Phytyl-PP which generates 2-Methyl-6-phytylhydroquinone. At this point of the synthesis, 2-Methyl-6-phytylhydroquinone can go through two different pathways. The first path takes the molecule and methylates it at C3. This results in a 2,3-Dimethyl-5-phytylhydroquinone. Then, the cyclization of the hydroxyl group at C1 generates the first derivative, γ-Tocopherol. Following the cyclization, another methylation is done at C5 of the γ-Tocopherol resulting in the production of α-Tocopherol. The second path takes the same 2-Methyl-6-phytylhydroquinone and cyclizes the hydroxyl group at C1 which produces the δ-Tocopherol. Afterward, a round of methylation at C5 results in the last derivative, β-Tocopherol. This whole synthesis occurs similarly for tocotrienol with prenyl-PP, which is generated from a GGDP group, replacing the phytyl-PP.^[28]

Industrial synthesis

The synthetic product is all-rac-alpha-tocopherol,^[29] also referred to as dl-alpha tocopherol. It consists of eight stereoisomers (RRR, RRS, RSS, RSR, SRR, SSR, SRS and SSS) in equal quantities. "It is synthesized from a mixture of toluene and 2,3,5-trimethyl-hydroquinone that reacts with isophytol to all-rac-alpha-tocopherol, using iron in the presence of hydrogen chloride gas as catalyst. The reaction mixture obtained is filtered and extracted with aqueous caustic soda. Toluene is removed by evaporation and the residue (all rac-alpha-tocopherol) is purified by vacuum distillation."^[29] The synthetic is in contrast to what is extracted from plants, all RRR-alpha tocopherol, referred to as d-alpha-tocopherol. The synthetic has 73.5% of the potency of the natural.^[30] Manufacturers of dietary supplements and fortified foods for humans or domesticated animals convert the phenol form of the vitamin to an ester using either acetic acid or succinic acid because the esters are more chemically stable, providing for a longer shelf-life.^[2][31]

Deficiency

Vitamin E deficiency is rare in humans, occurring as a consequence of abnormalities in dietary fat absorption or metabolism rather than from a diet low in vitamin E.^[3] One example of a genetic abnormality in metabolism is mutations of genes coding for alpha-tocopherol transfer protein (α-TTP). Humans with this genetic defect exhibit a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED) despite consuming normal amounts of vitamin E. Large amounts of alpha-tocopherol as a dietary supplement are needed to compensate for the lack of α-TTP.^[32][33] Vitamin E deficiency due to either malabsorption or metabolic anomaly can cause nerve problems due to poor conduction of electrical impulses along nerves due to changes in nerve membrane structure and function. In addition to ataxia, vitamin E deficiency can cause peripheral neuropathy, myopathies, retinopathy, and impairment of immune responses.^[3][4]

Drug interactions

The amounts of alpha-tocopherol, other tocopherols and tocotrienols that are components of dietary vitamin E, when consumed from foods, do not appear to cause any interactions with drugs. Consumption of alpha-tocopherol as a dietary supplement in amounts in excess of 300 mg/day may lead to interactions with

The European Food Safety Authority (EFSA) refers to the collective set of information as dietary reference values, with population reference intakes (PRIs) instead of RDAs, and average requirements instead of EARs. AIs and ULs are defined the same as in the United States. For women and men ages 10 and older, the PRIs are set at 11 and 13 mg/day, respectively. PRI for pregnancy is 11 mg/day, for lactation 11 mg/day. For children ages 1–9 years the PRIs increase with age from 6 to 9 mg/day.^[35] The EFSA used an effect on blood clotting as a safety-critical effect. It identified that no adverse effects were observed in a human trial as 540 mg/day, used an uncertainty factor of 2 to derive an upper limit of half of that, then rounded to 300 mg/day.^[36]

The Japan National Institute of Health and Nutrition set adult AIs at 6.5 mg/day (females) and 7.0 mg/day (males), and 650–700 mg/day (females), and 750–900 mg/day (males) for upper limits, amounts depending on age.^[37] India recommends an intake of 8–10 mg/day and does not set an upper limit.^[38] The World Health Organization recommends that adults consume 10 mg/day.^[5] The United Kingdom is an outlier, in that it recommends 4 mg/day for adult men and 3 mg/day for adult women.^[39]

Consumption is below these government recommendations. Government survey results in the United States reported average consumption for adult females at 8.4 mg/d and adult males 10.4 mg/d.^[40] Both are below the RDA of 15 mg/day. A worldwide summary of more than one hundred studies reported a median dietary intake of 6.2 mg/d for alpha-tocopherol.^[5]

Food labeling

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of daily value. For vitamin E labeling purposes 100% of the daily value was 30 international units, but as of 27 May 2016, it was revised to 15 mg to bring it into agreement with the RDA.^[41] A table of the old and new adult daily values is provided at Reference Daily Intake.

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of daily values, amounts are shown as percent of reference intakes (RIs). For vitamin E, 100% RI was set at 12 mg in 2011.^[42]

The international unit measurement was used by the United States in 1968–2016. 1 IU is the biological equivalent of about 0.667 mg d (RRR)-alpha-tocopherol (2/3 mg exactly), or of 0.90 mg of dl-alpha-tocopherol, corresponding to the then-measured relative potency of stereoisomers. In May 2016, the measurements have been revised, such that 1 mg of "Vitamin E" is 1 mg of d-alpha-tocopherol or 2 mg of dl-alpha-tocopherol.^[43] The change was originally started in 2000, when forms of Vitamin E other than alpha-tocopherol was dropped from dietary calculations by the IOM. The UL amount disregards any conversion.^[44] The EFSA has never used an IU unit, and their measurement only considers RRR-alpha-tocopherol.^[45]

Sources

Worldwide, consumption is below recommendations according to a summary of more than one hundred studies that reported a median dietary intake of 6.2 mg per day for alpha-tocopherol.

The U.S. Department of Agriculture (USDA), Agricultural Research Services, maintains a food composition database. The last major revision was Release 28, September 2015. In addition to the naturally occurring sources shown in the table,[47] certain ready-to-eat cereals, infant formulas, liquid nutrition products and other foods are fortified with alpha-tocopherol.^[47]

Supplements

Vitamin E is fat soluble, so dietary supplement products are usually in the form of the vitamin, esterified with acetic acid to generate

The World Health Organization does not have any recommendations for food fortification with vitamin E.[48] The Food Fortification Initiative does not list any countries that have mandatory or voluntary programs for vitamin E.^[49] Infant formulas have alpha-tocopherol as an ingredient. In some countries, certain brands of ready-to-eat cereals, liquid nutrition products and other foods have alpha-tocopherol as an added ingredient.^[47]

Non-nutrient food additives

Various forms of vitamin E are common

These E numbers include all racemic forms and acetate esters thereof.[50] Commonly found on food labels in Europe and some other countries, their safety assessment and approval are the responsibility of the European Food Safety Authority.^[51]

Metabolism

Tocotrienols and tocopherols, the latter including the stereoisomers of synthetic alpha-tocopherol, are absorbed from the intestinal lumen, incorporated into chylomicrons, and secreted into the portal vein, leading to the liver. Absorption efficiency is estimated at 51% to 86%,^[3] and that applies to all of the vitamin E family – there is no discrimination among the vitamin E vitamers during absorption. Unabsorbed vitamin E is excreted via feces. Additionally, vitamin E is excreted by the liver via bile into the intestinal lumen, where it will either be reabsorbed or excreted via feces, and all of the vitamin E vitamers are metabolized and then excreted via urine.^[3][11]

Upon reaching the liver, RRR-alpha-tocopherol is preferentially taken up by alpha-tocopherol transfer protein (α-TTP). All other forms are degraded to 2'-carboxethyl-6-hydroxychromane (CEHC), a process that involves truncating the phytic tail of the molecule, then either sulfated or glycuronidated. This renders the molecules water-soluble and leads to excretion via urine. Alpha-tocopherol is also degraded by the same process, to 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychromane (α-CEHC), but more slowly because it is partially protected by α-TTP. Large intakes of α-tocopherol result in increased urinary α-CEHC, so this appears to be a means of disposing of excess vitamin E.^[3][11]

Alpha-tocopherol transfer protein is coded by the TTPA gene on chromosome 8. The binding site for RRR-α-tocopherol is a hydrophobic pocket with a lower affinity for beta-, gamma-, or delta-tocopherols, or for the stereoisomers with an S configuration at the chiral 2 site. Tocotrienols are also a poor fit because the double bonds in the phytic tail create a rigid configuration that is a mismatch with the α-TTP pocket.^[11] A rare genetic defect of the TTPA gene results in people exhibiting a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED) despite consuming normal amounts of vitamin E. Large amounts of alpha-tocopherol as a dietary supplement are needed to compensate for the lack of α-TTP.^[32] The role of α-TTP is to move α-tocopherol to the plasma membrane of hepatocytes (liver cells), where it can be incorporated into newly created very low density lipoprotein (VLDL) molecules. These convey α-tocopherol to cells in the rest of the body. As an example of a result of the preferential treatment, the US diet delivers approximately 70 mg/d of γ-tocopherol and plasma concentrations are on the order of 2–5 µmol/L; meanwhile, dietary α-tocopherol is about 7 mg/d but plasma concentrations are in the range of 11–37 µmol/L.^[11]

Affinity of α-TTP for vitamin E vitamers^[11]

Testing for levels

A worldwide summary of more than one hundred human studies reported a median of 22.1 µmol/L for serum α-tocopherol, and defined α-tocopherol deficiency as less than 12 µmol/L. It cited a recommendation that serum α-tocopherol concentration be ≥30 µmol/L to optimize health benefits.^[5] In contrast, the U.S. Dietary Reference Intake text for vitamin E concluded that a plasma concentration of 12 µmol/L was sufficient to achieve normal ex vivo hydrogen peroxide-induced hemolysis.^[3] A 2014 review defined less than 9 µmol/L as deficient, 9-12 µmol/L as marginal, and greater than 12 µmol/L as adequate.^[52]

Serum concentration increases with age. This is attributed to the fact that vitamin E circulates in blood incorporated into lipoproteins, and serum lipoprotein concentrations increase with age. Infants and young children have a higher risk of being below the deficiency threshold.^[5] Cystic fibrosis and other fat malabsorption conditions can result in low serum vitamin E. Dietary supplements will raise serum vitamin E.^[3]

Medical applications

For the conditions described below, the results of randomized clinical trials (RCTs) do not always concur with the observational evidence.^[2] This could be a matter of amount. Observational studies compare low consumers to high consumers based on intake from food. Diets higher in vitamin E may contain other compounds that convey health benefits, or be consumed by people who make non-diet lifestyle choices that lower disease risk, so that the observed effect may not be due to the vitamin E content. Meanwhile, many of the published RCTs used amounts of alpha-tocopherol 20X to 30X higher than what can be achieved from food.^[8]

Declining supplement use

In the United States, vitamin E supplement use by female health professionals was 16.1% in 1986, 46.2% in 1998, 44.3% in 2002, but decreased to 19.8% in 2006. Similarly, for male health professionals, rates for same years were 18.9%, 52.0%, 49.4% and 24.5%. The authors theorized that declining use in these populations may have been due to publications of studies that showed either no benefits or negative consequences from vitamin E supplements.^[6] Within the U.S. military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%.^[53] A report on vitamin E sales volume in the US documented a 50% decrease between 2000 and 2006,^[7] with a potential reason being a meta-analysis that concluded high-dosage (≥400 IU/d for at least 1 year) vitamin E was associated with an increase in all-cause mortality.^[54]

All-cause mortality

Two meta-analyses concluded that as a dietary supplement, vitamin E neither improved nor impaired all-cause mortality.^[55][56] An older meta-analysis had concluded high-dosage (≥400 IU/d for at least 1 year) vitamin E was associated with an increase in all-cause mortality. The authors acknowledged that the cited high-dose trials were often small and performed with people who already had chronic diseases.^[54] A meta-analysis of long-term clinical trials reported a non-significant 2% increase in all-cause mortality when alpha-tocopherol was the only supplement used. The same meta-analysis reported a statistically significant 3% increase for results when alpha-tocopherol was used in combination with other nutrients (vitamin A, vitamin C, beta-carotene, selenium).^[8]

Age-related macular degeneration

No changes seen for risk of developing age-related macular degeneration from long-term vitamin E suplementation.^[57]

Alzheimer's disease

An older review of dietary intake studies reported that higher consumption of vitamin E from foods lowered the risk of developing Alzheimer's disease (AD) by 24%.^[58] A 2017 Cochrane review reported on vitamin E as a potential dietary benefit for mild cognitive impairment (MCI) and Alzheimer's disease. Based on evidence from one trial in each of the categories, the study found insufficient evidence for supplemental vitamin E to prevent progression from MCI to dementia, but it did indicate slowing of functional decline in people with AD. Given the small number of trials and subjects, the authors recommended further research.^[59] A 2018 meta-analysis found lower vitamin E blood levels in AD people compared to healthy, age-matched people.^[60] In 2017, a consensus statement from the British Association for Psychopharmacology concluded that, until further information is available, vitamin E cannot be recommended for treatment or prevention of Alzheimer's disease.^[61]

Cancer

In a 2022 update of an earlier report, the United States Preventive Services Task Force recommended against the use of vitamin E supplements for the prevention of cardiovascular disease or cancer, concluding there was insufficient evidence to assess the balance of benefits and harms, yet also concluding with moderate certainty that there is no net benefit of supplementation.^[62]

As for literature on different types of cancer, an inverse relationship between dietary vitamin E and kidney cancer and bladder cancer is seen in observational studies. The risk reduction was 19% when highest and lowest intake groups were compared. The authors concluded that randomized controlled trials are needed.^[63][64] A large study comparing placebo to an all rac-alpha-tocopherol group consuming 400 IU/day reported no difference in bladder cancer cases.^[65] An inverse relationship between dietary vitamin E and lung cancer was reported in observational studies. The relative risk reduction was 16% when highest and lowest intake groups were compared. The benefit was progressive as dietary intake increased from 2 mg/day to 16 mg/day. The authors noted that the findings need to be confirmed by prospective studies.^[66] One such large trial, which compared 50 mg alpha-tocopherol to placebo in male tobacco smokers, reported no impact on lung cancer.^[67] A trial which tracked people who chose to consume a vitamin E dietary supplement reported an increased risk of lung cancer for those consuming more than 215 mg/day.^[68]

For prostate cancer, there are also conflicting results. A meta-analysis based on serum alpha-tocopherol content reported an inverse correlation, with the difference between lowest and highest a 21% reduction in relative risk.^[69] In contrast, a meta-analysis of observational studies reported no relationship for dietary vitamin E intake.^[70] There were also conflicting results from large RCTs. The ATBC trial administered placebo or 50 mg/day alpha-tocopherol to male tobacco smokers for 5 to 8 years and reported a 32% decrease in the incidence of prostate cancer.^[71] Conversely, the SELECT trial of selenium and vitamin E for prostate cancer enrolled men ages 55 or older, mostly non-smokers, to consume a placebo or a 400 IU/day dietary supplement. It reported relative risk as a statistically significant 17% higher for the vitamin group.^[72]

For colorectal cancer, a systematic review identified RCTs of vitamin E and placebo followed for 7–10 years. There was a non-significant 11% decrease in relative risk.^[73] The SELECT trial (men over 55 years, placebo or 400 IU/day) also reported on colorectal cancer. There was a non-significant 3% increase in adenoma occurrence compared to placebo.^[74] The Women's Health Study reported no significant differences for incidences of all types of cancer, cancer deaths, or specifically for breast, lung or colon cancers.^[75]

Potential confounding factors are the form of vitamin E used in prospective studies and the amounts. Synthetic, racemic mixtures of vitamin E isomers are not bioequivalent to natural, non-racemic mixtures, yet are widely used in clinical trials and as dietary supplement ingredients.^[76] One review reported a modest increase in cancer risk with vitamin E supplementation while stating that more than 90% of the cited clinical trials used the synthetic, racemic form dl-alpha-tocopherol.^[68]

Cancer health claims

The U.S. Food and Drug Administration initiated a process of reviewing and approving food and dietary supplement health claims in 1993. Reviews of petitions results in proposed claims being rejected or approved. If approved, specific wording is allowed on package labels. In 1999, a second process for claims review was created. If there is not a scientific consensus on the totality of the evidence, a Qualified Health Claim (QHC) may be established. The FDA does not "approve" qualified health claim petitions. Instead, it issues a Letter of Enforcement Discretion that includes very specific claim language and the restrictions on using that wording.^[77] The first QHCs relevant to vitamin E were issued in 2003: "Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer." In 2009, the claims became more specific, allowing that vitamin E might reduce the risk of renal, bladder and colorectal cancers, but with required mention that the evidence was deemed weak and the claimed benefits highly unlikely. A petition to add brain, cervical, gastric and lung cancers was rejected. A further revision, May 2012, allowed that vitamin E may reduce risk of renal, bladder and colorectal cancers, with a more concise qualifier sentence added: "FDA has concluded that there is very little scientific evidence for this claim." Any company product label making the cancer claims has to include a qualifier sentence.^[78]

Cataracts

A meta-analysis from 2015 reported that for studies which reported serum tocopherol, higher serum concentration was associated with a 23% reduction in relative risk of age-related cataracts (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract – the three major classifications of age-related cataracts.^[79] However, this article and a second meta-analysis reporting on clinical trials of alpha-tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo.^[79][80]

Cardiovascular diseases

In an 2022 update of an earlier report, the United States Preventive Services Task Force recommended against the use of vitamin E supplements for the prevention of cardiovascular disease or cancer, concluding there was insufficient evidence to assess the balance of benefits and harms, yet also concluding with moderate certainty that there is no net benefit of supplementation.^[62]

Research on the effects of vitamin E on

In 2001, the U.S. Food and Drug Administration rejected proposed health claims for vitamin E and cardiovascular health.^[89] The U.S. National Institutes of Health reviewed literature published up to 2008 and concluded "In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality."^[4] The European Food Safety Authority (EFSA) reviews proposed health claims for the European Union countries. In 2010, the EFSA reviewed and rejected claims that a cause and effect relationship has been established between the dietary intake of vitamin E and maintenance of normal cardiac function or of normal blood circulation.^[90]

Nonalcoholic fatty liver disease

Meta-analyses reported that supplemental vitamin E significantly reduced elevated liver enzymes, steatosis, inflammation and fibrosis, suggesting that the vitamin may be useful for treatment of

For Parkinson's disease, there is an observed inverse correlation seen with dietary vitamin E, but no confirming evidence from placebo-controlled clinical trials.^[95][96]

Pregnancy

Antioxidant vitamins as dietary supplements have been proposed as having benefits if consumed during pregnancy. For the combination of vitamin E with vitamin C supplemented to pregnant women, a Cochrane review concluded that the data do not support vitamin E supplementation – majority of trials alpha-tocopherol at 400 IU/day plus vitamin C at 1,000 mg/day – as being efficacious for reducing risk of

Vitamin E is included in some skincare and wound-treatment products,^[98] but a 2015 meta-review found only "limited clinical evidence" of efficacy.^[99] However the authors noted a dearth of research, stating that 23 of the 39 studies reviewed were "of limited quality with individual flaws, including low patient numbers, poor randomization, blinding, and short follow-up periods."

Topical

Although there is widespread use of

On 5 September 2019, the US

Vitamin E was discovered in 1922 by Herbert McLean Evans and Katharine Scott Bishop^[108] and first isolated in a pure form by Evans and Gladys Anderson Emerson in 1935 at the University of California, Berkeley.^[109] Because the vitamin activity was first identified as a dietary fertility factor in rats, it was given the name "tocopherol" from the Greek words "τόκος" [tókos, birth], and "φέρειν", [phérein, to bear or carry] meaning in sum "to carry a pregnancy," with the ending "-ol" signifying its status as a chemical alcohol. George M. Calhoun, Professor of Greek at the University of California, was credited with helping with the naming process.^[110] Erhard Fernholz elucidated its structure in 1938 and shortly afterward the same year, Paul Karrer and his team first synthesized it.^[111]

Nearly 50 years after the discovery of vitamin E, an editorial in the Journal of the American Medical Association titled "Vitamin in search of a disease" read in part "...research revealed many of the vitamin's secrets, but no certain therapeutic use and no definite deficiency disease in man." The animal discovery experiments had been a requirement for successful pregnancy, but no benefits were observed for women prone to miscarriage. Evidence for vascular health was characterized as unconvincing. The editorial closed with mention of some preliminary human evidence for protection against hemolytic anemia in young children.^[112]

A role for vitamin E in coronary heart disease was first proposed in 1946 by Evan Shute and colleagues.^[113][114] More cardiovascular work from the same research group followed,^[115] including a proposal that megadoses of vitamin E could slow down and even reverse the development of atherosclerosis.^[116] Subsequent research showed no association between vitamin E supplementation and cardiovascular events such as nonfatal stroke or myocardial infarction, or cardiovascular mortality.^[117]

There is a long history of belief that topical application of vitamin E containing oil benefits burn and wound healing.^[98] This belief persists even though scientific reviews refuted this claim.^{[99][100][101]}

The role of vitamin E in infant nutrition has a long research history. From 1949 onward there were trials with premature infants suggesting that oral alpha-tocopherol was protective against