Vitamin E

Vitamin E was first known as an essential vitamin during a series of studies in which administration of rancid meat products to animals caused deficiency symptoms (later discovered to be due to depleting bodily stores of vitamin E) which was found to be reversed or 'cured' by wheat germ (a source of vitamin E).^[10]

Vitamin E can be quantified by weight (mg) or bioactivity (International Units, or IU). This is due to all forms of vitamin E not sharing the same bioactivity.^[11]

Out of all forms of vitamin E, the liver tends to target α-tocopherol most for incorporation into lipoproteins.^[12] This is also the specific isomer commonly used in studies to reverse deficiency symptoms^[13][14][15] and has the highest bioavailability.^[16]

Alpha-tocopherol affects cell signalling processes independent of its antioxidant role, and is able to inhibit smooth muscle cell proliferation, decrease Protein kinase C (PKC, an enzyme family that plays a role in signal transduction) activity in cells, increase phosphoprotein phosphatase 2A activity, and regulate the the α-tropomyosin gene.^[17][18][19] The inhibition of PKC may be secondary to reducing levels of diacylglycerol (a PKC activator) leaked from the membrane^[20][21] and requires vitamin E to be a constituent of the membrane.^[22]

Vitamin E can also regulate the expression of some pro-thrombotic and atherogenic factors^[23][24] and may be secondary to upregulation of phospholipase A2 and cyclooxygenase enzymes.^[25] These effects may explain why vitamin E has been shown to dose-dependently increase prostacyclin levels in vivo.^[26][27][28]

Vitamin E reference plasma concentrations are in the range of 12-46µM,^[29] resulting in the recommended dietary intake being (according to the NIH) 15mg of natural α-tocopherol or 22.4 international units (IU) for people over the age of 14 regardless of sex.^[30] While the recommendations appear to be based exclusively on α-tocopherol equivalents, there are differences between natural sources providing RRR-α-tocopherol (where 15mg is recommended, as 1mg is equivalent to 1.67IU) and synthetic all-rac α-tocopherol (where 10mg is recommended, as 1mg is equivalent to 2.22IU).^[30]

The daily recommended intake of vitamin E, as α-tocopherol, is slightly above 20 international units (IU). While synthetic vitamin E appears to have a lower overall requirement, the difference is controlled for when measuring vitamin E in international units.

Deficiencies of vitamin E tend to result in myopathies and neuromyopathies^[31] and forms of ataxia.^[32]

Overt deficiencies are rare, and are usually due to genetic defects in the transport proteins responsible for vitamin E^[33]) or malabsorption secondary to alcoholism or intestinal diseases such as Crohn's disease or cystic fibrosis (without enzyme therapy).^[12][34]

True vitamin E deficiencies in an otherwise healthy population are rare, with almost all cases of vitamin E deficiency being noted in disease states where fatty acid absorption from the intestines is significantly impaired (e.g. Crohn's disease).

Subclinical deficiencies may occur in response to excess oxidation^[35][12] and may diminish erythrocyte lifespan.^[36][37]

The tolerable upper limit (TUL) for vitamin E intake is 800mg (1,200 IU) for persons between the ages of 14-18 and 1,000mg (1,500 IU) for adults, with no changes in adult females due to pregnancy or lactation.^[30]

Vitamin E is found in nature in 8 different forms. The tocopherols (where alpha(α), beta(β), gamma(γ) and delta(δ) variants exist) and the tocotrienols (same alpha(α), beta(β), gamma(γ) and delta(δ) variants).^[38][39] All forms are biologically active, although α-tocopherol is commonly seen as the most bioactive form and the true 'essential vitamin'^[40] as it has preference for a particular transporation protein known as tocopherol transfer protein (TTP) which brings orally supplemented vitamin E in the liver to other tissues in the body.^[41]

Tocotrienols can be transported in the blood, since their elevation in the blood following oral administration is present (and faster than tocopherols at an equal dose^[42]) and they can be detected in serum platelets and adipose tissue following oral ingestion.^[43][42][44] There also appears to be less efflux from tissues with tocotrienols (suggesting a greater reliance for loading and chronic effects),^[45] but it is still possible for the benefits associated with tocotrienols seen in vitro to be overstated due to transportation issues.^[45]

'Vitamin E' refers to vitamers (isomers of a vitamin) that share structural and functional similarities, and while only the form known as α-tocopherol is an essential vitamin all of the vitamers have biological functions. There are also some differences in transportation of these vitamers to tissues, although they all seem to be able to influence peripheral tissue beyond the liver.

The terms 'natural' and 'synthetic' vitamin E appear to be legitimate terms, as vitamin E that occurs in food tends to be an RRR configuration (RRR-α-tocopherol usually used as the abbreviation) whereas synthetic vitamin E commonly used in supplements exists as eight isomers of α-tocopherol abbreviated as all-rac-α-tocopherol due to having multiple chiral centers.^[46]

Synthetic α-tocopherol tends to have 50% of the affinity for the tocopherol transport protein (TTP) compared to the natural form^[47] and when comparing bodily retention of α-tocopherol it seems that when natural and synthetic are both ingested (150mg each) that the synthetic is more readily eliminated via nonoxidative metabolism;^[48] due to these reasons, it is thought that natural vitamin E is more readily available to the body.

Natural vitamin E food sources (not so much dietary supplements of pure α-tocopherol) may also contain tocotrienols in its mixture, whereas synthetic Vitamin E does not contain tocotrienols and is limited to the essential α-tocopherol vitamer;^[45] this is more of a concern to food intake which is mixed vitamers, since a supplement standardized for α-tocopherol will not contain tocotrienols regardless of whether it is natural or synthetic.

There does appear to be a difference between 'natural' and 'synthetic' vitamin E even when it is pure α-tocopherol, as the synthetic form is a mixture of four isomers whereas the natural form consists of α-tocopherol (RRR-α-tocopherol) rather than the mixture. Depending on the source, natural vitamin E sources may also include other vitamers and tocotrienols whereas the synthetic version does not.

γ-tocopherol is the other majorly researched tocopherol (most research is conducted on α-tocopherol with less on beta and delta) in part due to it being the highest dietary source of vitamin E in the American diet via flour and vegetable oil products.^[49] It does have the ability to exert vitamin-like properties in the deficient animal, although as it is approximately 7-13% the potency of α-tocopherol^[50] the increased content in the diet is only hypothesized to account for up to 20% of vitamin E-like activity in the human diet.^[49]

γ-tocopherol is known to have its concentrations in serum decline when α-tocopherol by itself is supplemented (1,200IU all-rac α-tocopherol over eight weeks reducing serum γ-tocopherol to 30-50% of baseline^[51]) and the two have somewhat of an inverse relationship in serum where elevating α-tocopherol concentrations are correlated with lower γ-tocopherol concentrations.^[52] This antagonistic relationship has also been noted with β-tocopherol, being reduced with supplemental α-tocopherol at 1,200IU.^[51]

γ-Tocopherol has been shown to exert a 'trapping' effect on nucleophilic mutagens (mutation-causing agents) and aids in the chemoprotective properties of the anti-oxidant system glutathione.^[53][54][55]

It appears to have its efficacy in chemoprotection reduced when paired with alpha-tocopherol.^[56]

Of the tocopherols, γ-tocopherol is investigated to a large degree both independently and in the context of α-tocopherol supplements.

Tocotrienols are named as such since they possess 3 double bonds in their isoprenoid side chains whereas tocopherols only possess two.^[45]

Tocotrienols can be seen as more potent than tocopherols in vitro in regards to their anti-oxidant properties directly^[57][58] and vicariously through selenoproteins,^[59] at inducing apoptosis and protecting against some forms of cancer,^[60][61] and at neuroprotection.^[62][63] In vivo, tocotrienols appear to be more potent than tocopherols for prevention of certain cancers,^[64] for antioxidation^[58][65] as well as anti-inflammation,^[66] and better protection of bone health.^{[65][67][68][69][70]}

On parameters where the mechanism is related to antioxidant effects of vitamin E, tocotrienols are thought to be more effective than the same dose of tocopherols due to having more unsaturated points in their side chain (and more potential to sequester oxidation).

Vitamin E has been known to inhibit phosphokinase C (PKC) activation in blood platelets,^[71][72] other cells within tissue such as aortic cells,^[73][74] and is able to suppress PGE₂ secretion in macrophages (whose synthesis is regulated by PKC^[75]), which may also affect T-cell function.^[76]

Vitamin E appears to have a suppressive role on diacylglycerol (DAG) concentrations within a cell, having been implicated in suppressing increases in DAG^[73][77] and promoting its clearance^[74] by reducing its release from the membrane (where DAG is stored) and increasing the activity of DAG kinase respectively. Since DAG positively influences PKC activity,^[78] its reduced activity is thought to underlie the suppressive effects of vitamin E on PKC.

Vitamin E appears to be a PKC inhibitor, secondary to reducing the DAG-induced increases in PKC activity. This appears to extend to numerous cell lines.

When in the intestines, all vitamin E isomers are almost exclusively taken up via the lymph and packed in chylomicrons.^[79] Esters (ie. vitamin E acetate) are hydrolyzed either in the intestines or stomach acid prior to absorption.^[80] Vitamin E does not appear to be reesterified after absorption^[79] and studies in serum and cerebrospinal fluid confirm the lack of esterified vitamin E (unlike vitamin A or cholesterol, which are reesterified after absorption).^[81][52]

Absorption appears to be increased in the presence of medium chain triglycerides as more vitamin E appears in lymphatic tissue.^[82] When comparing the absorption rates and processes of α-tocopherol against γ-tocopherol in rat studes, there do not appear to be any significant differences at the intestinal level.^[49]

Similar to most fat-soluble nutrients as well as dietary long chain fatty acids, vitamin E isomers are absorbed from the intestines into lymph tissue via chylomicrons which then distribute vitamin E to circulation.

Lymphatic transportation in the intestines plays a vital role in absorption of lipophilic drugs and nutrients.^[83] The absorption of such drugs into lymphatic transport can be enhanced with the addition of bile acids^[84] and some lipid-based formulations,^[85][86] or with surfactants such as Cremophor RH40.^[87] A variant of Vitamin E known as Vitamin E-TPGS (polyethylene glycol 1000 succinate), beyond its emulsifying properties,^[88] appears to enhance the bioavailability of a variety of water insoluble drugs such as paclitaxel.^[89] This is thought to be related to its surfactant properties and inducing secretion of chylomicrons at concentrations of 0.1-0.5%.^[90]

Water soluble vitamin E (Vitamin E-TPGS) appears to have the ability to enhance the absorption of fat-soluble drugs when coingested, thought to be due to enhancing secretion of chylomicrons (which are required to transport fat-soluble drugs).

Topical application of vitamin E succinate (in a vehicle of Myritol 318 prepared from coconut oil) appeared to be absorbed topically in the mouse and transported to internal organs.^[91]

Vitamin E succinate appears to yield free vitamin E following topical application in the mouse, with conversion rates of approximately 6% after 24 hours of absorption.^[91] This conversion rate is similar to what has been noted in the mouse with Vitamin E acetate (5-6%).^[92]

Vitamin E in the forms of acetate and succinate both appear to be absorbed through the skin (with better absorption when using an appropriate vehicle), and a small percentage is converted into free form Vitamin E.

Oral ingestion of pure α-tocopherol supplements is known to dose-dependently reduce circulating concentrations of γ-tocopherol, with a 36-42% increase in basal α-tocopherol being met with a 28-61% reduction in γ-tocopherol.^[9] This reduction in γ-tocopherol also seems to extend to red blood cells when they experience an increase in α-tocopherol,^[93] and has been repeatedly noted either inherently or when combined with fish oil supplementation.^[94][95][96] Supplementation of γ-tocopherol in isolation (up to 200mg over five weeks) conversely does not reduce circulating α-tocopherol concentrations,^[97][98] and in trials using mixed tocopherol supplements it appears that 63% γ-tocopherol (315mg of a 500mg vitamin E supplement) is sufficient to elevate γ-tocopherol despite coingesting α-tocopherol (15%).^[99]

Ingesting α-tocopherol (either natural or synthetic) in isolation appears to reduce circulating levels of γ-tocopherol, whereas the opposite does not appear to exist. Supplementing approximately equal levels of the two is thought to be sufficient to prevent a decrease in plasma γ-tocopherol.

It is thought that the reduction in serum γ-tocopherol comes secondary to α-tocopherol inducing secretion of vLDL particles rich in α-tocopherol,^[100] as there does not appear to be competitive inhibition in the absorption of the two molecules from the intestines.^[101]

Phospholipid transfer protein (PLTP) is a plasma protein that appears to have a role in distributing vitamin E from lipoproteins into tissue in animal models, as a deficiency of this protein results in accumulation of α-tocopherol in lipoproteins and reduction at the vascular wall^[102] as well as the brain,^[103] where it is typically expressed at high levels in the rat and rabbit, ^[104][105] but interestingly not in humans.^[106][107]

PLTP plays a role in donating vitamin E from lipoproteins (its mode of transportation around the body) into body tissue.

Oral consumption of mixed tocotrienols from rice bran (90% γ-tocotrienol) have been noted to increase skin concentrations of tocotrienols in mice when dosed orally at 1mg/kg over the course of one week, increasing the baseline concentration of γ-tocotrienol from 0.4+/-0.1nM/g to 27.9+/-1.4nM/g.^[108] This increase did not negatively influence α-tocopherol concentrations in the skin.^[108]

At least in mice, oral supplementation of low doses of tocotrienols (mainly γ-tocotrienol) appears to greatly increase the concentration of tocotrienols found in the skin.

Vitamin E isomers can be detected in cerebrospinal fluid (CSF)^[81] where concentrations of vitamin E as α-tocopherol in CSF have been reported to be in the range of 30.1+/-11.6nM (persons with ALS),^[109] 42.1+/-17nM (otherwise healthy, older controls),^[52] and 56.7+/-28.4nM (Alzheimer's)^[110] while in studies comparing CSF concentrations to serum there appears to be a significant correlation between the two which is neither affected by age nor cholesterol levels in serum;^[52] CSF concentrations of α-tocopherol appear to be 580-fold lower than serum (42.1nM in CSF relative to 21.7µM) and γ-tocopherol which also shares a correlation between CSF and serum is more than 1000-fold lower in CSF (5.9nM relative to 6.29µM in serum).^[52] The known serum relationship between these two isomers (acute doses of α-tocopherol reducing γ-tocopherol concentrations^[51]) may also apply to CSF concentrations.^[52]

Vitamin E isomers are detected in human cerebrospinal fluid, and despite their concentrations being lower than that found in serum they seem to correlate with serum. Correlations between the isomers themselves seen in serum may also extend to cerebrospinal fluid.

Excess vitamin E (tocopherols) that is not used in the body as an antioxidant is degraded ^[111] by the CYP3A enzyme,^[112] which functions as a tocopherol-ω-hydroxylase by metabolizing tocopherols into carboxyethyl-hydroxychromans (CEHCs).^{[113][114][115][116]} This particular function of the enzyme is inhibited by the lignan sesamin, thus increasing endogenous tocopherol concentrations.^[117][112] This process also applies to tocotrienols (forming CEHC metabolites in accordance with their isomer^[114][118]). These metabolites ultimately appear in the urine as glucuronides or sulfated metabolites (indicative of Phase II metabolism after the initial CYP3A mediated step).^[119]

When CEHC levels are reduced in the urine despite vitamin E intake being held constant or increased, it is thought to be representative of increased oxidation in the body (as vitamin E is being consumed in its role as as antioxidant instead of being eliminated in the form of CEHCs).^[116] CEHC metabolism of α-tocopherol doesn't occur to a significant degree when people are not supplemented and have concentrations below the range of 30-40μM,^{[111][120][116]} and the levelling off of tocopherols in plasma as a result of supplementation are thought to be due to increased metabolism to CEHCs.

Vitamin E vitamers appear to be metabolized by a CYP3A-mediated function into carboxyethyl-hydroxychroman derivatives (CEHCs), and this metabolism occurs to both tocopherols and tocotrienols. This metabolism is performed on excess vitamin E that is not utilized as an antioxidant, and when CEHCs increase or decrease in the urine (if vitamin E intake is held constant) it is thought to reflect either no additional antioxidant effects or increased oxidation respectively.

Tocotrienols (α and γ) appear to be metabolized and excreted in the urine as carboxyethyl-hydroxychroman (CEHC) derivatives similar to the tocopherols, with 1-2% of the oral dose of α-tocotrienol (125-500mg) and 4-6% of the oral dose of γ-tocotrienol (125-500mg) being detected in the urine one day after supplementation.^[114] The elimintation pattern of γ-CEHC from tocotrienol ingestion is approximately 10% after 9 hours of ingestion^[114] which is similar to that from gamma-tocopherol.^[121]

A small amount of the CEHC derivatives from vitamin E are eliminated in the urine.

Exposure to lead is known to cause prooxidative stress in the organism^[122] and although α-tocopherol seems unaffected, increasing lead concentration has been assocaited with reduced γ-tocopherol levels in serum.^[123]

Vitamin E has been shown to have protective effects against lead in rat models on neurological,^[124] testicular,^[125][126] and liver damage.^[124] In humans, supplementation of 400IU Vitamin E (α-tocopherol) paired with 1,000mg Vitamin C to lead-exposed workers with elevated concentrations of lead in the blood reduced the lead-induced oxidative changes in serum and red blood cells, but this protective effect was without any changes in bodily lead levels.^[127]

The increased oxidative stress seen alongside higher-than-normal blood concentrations of lead (from occupational exposure) appears to be reduced with vitamin E and C combination therapy. This benefit does not appear to be due to reducing lead accumulation in the body.

Vitamin E (as α-tocotrienol) appears to be able to inhibit glutamate-induced phospholipase A₂ (PLA₂; the protein which releases eicosanoids^[128]) activation, resulting in less arachidonic acid release by decreasing activation via phosphorylation of Ser₅₀₅ on PLA₂.^[129] It may also reduce the activation of 12-lipoxygenase (12-LOX) in response to neuronal injury, which is an enzyme that would normally bioactivate arachidonic acid starting a cascade leading to cell death.^[130][131] The inhibition of this pathway by α-tocotrienol occurs at a concentration of 250nM, resulting in neuroprotection,^[130][131] (which is 4- to 10-fold lower than plasma levels of α-tocotrienol from oral supplementation of 250mg^[132], suggesting that oral supplementation may confer this neuroprotective effect^[130][131]). This neuroprotective effect is not seen with α-tocopherol, the major vitamin E isomer.^[133]

α-tocotrienol has been noted to reduce glutamate-induced release of eicosanoids (the signalling molecules in a cell produced from fish oil and arachidonic acid) and confer neuroprotection against glutamate-induced cell death in vitro. This may occur at a concentration low enough to be influenced by supplementation.

A diet deficient in vitamin E over the course of twelve weeks has not resulted in significantly altered concentrations of serotonin in rats.^[134] Although there may be mild alterations in the intracellular/extracellular ratio within 15-21 days^[135][134] with both the prefrontal cortex^[135] and hippocampus^[136] being implicated, these changes seem to be normalized after twelve weeks.^[134]

Based on rat data, there do not appear to be any long-term abnormalities in serotonin levels associated with vitamin E deficiency.

One trial has found that vitamin E supplementation (at 50mg) does appears to protect older male smokers without a previous history of stroke from ischemic stroke, but increased the risk of hemorrhagic stroke, making the total all-cause stroke prevention nonsignificant.^[137]This protective effect disappears after supplementation ceases, however, and rebound effect of increased risk of stroke of borderline significance was seen.^[138] A subgroup analysis of this trial revealed that men with high blood pressure could be protected from ischemic stroke without the associated increased risk of hemorrhagic stroke, however.^[139] The increased risk of hemorrhagic stroke in male smokers supplemented with vitamin E has been seen before,^[140] although this risk may be longer-term rather than short-term, as even 800IU of vitamin E does not affect blood clotting factors for short durations (14 days).^[141] However, other studies assessing the effects of vitamin E even at higher doses (up to 400IU daily) have failed to replicate both the increased risk of hemorrhagic stroke or the decreased risk of ischemic stroke in different populations, such as otherwise healthy women^[142][143] or people with pre-existing vascular disease or diabetes.^[144]

While there is mixed evidence for the role of vitamin E in stroke, none of the evidence suggests a significant protective effect from overall stroke risk and most evidence suggests no significant interaction.

Inducing vitamin E deficiency in the rat (via ablating α-tocopherol transport protein^[145] or via a deficient diet^[146][147]) can caused anxiety symptoms. A gene deletion which results in significantly less α-tocopherol in the brain also results in anxiety symptoms.^[103] This increase in anxiety is seen alongside elevated corticosterone concentrations in serum both at rest and after anxiety testing relative to control.^[146]

A large study of 600 IU vitamin E supplementation every other day in otherwise healthy women over the age of 65 spanning an average of 5.6 years failed to find any benefit of vitamin E supplementation relative to placebo in improving cognitive parameters including verbal memory, categorical fluency, and general cognition relative to placebo.^[148]

Supplementation of vitamin E in otherwise healthy older women, when investigated, has failed to find any significant interaction with memory formation or processing.

One study in diabetics (type I and II) given high dose α-tocopherol supplementation at 1,600 IU for the course of one year failed to find any significant changes in left ventricular function relative to placebo.^[149] 

The Heart Outcomes Prevention Evaluation (HOPE) trial, involving patients over the age of 55 with preexisting vascular disease or type II diabetes given 400IU supplemental vitamin E for an average of 4.5 years, also failed to find any effect on cardiovascular mortality.^[150] An extension of the HOPE study using 400IU of α-tocopherol for seven years (using approximately half of the initial sample) found a greater decrease in left ventricular ejection fraction (LVEF) of 1.86% over four years compared to a 0.58% decrease in placebo, translating to a minor increase in the risk of heart failure relative to placebo with a HR of 1.13 (95% CI of 1.01-1.26).^[144]

One study has noted a potential increase in heart failure with supplementation of moderate doses of vitamin E in metabolically unwell patients over the long-term. The effects of prolonged vitamin E supplementation in those without any metabolic complications has not been studied to date.

In otherwise healthy men given supplemental α-tocopherol, the rise in plasma α-tocopherol and subsequent decrease in plasma γ-tocopherol was reflected in red blood cells which experienced similar changes; both required four weeks of constant supplementation to reach peak concentrations.^[93]

The changes of vitamin E seen in serum appear to reflect the changes of vitamin E seen in red blood cells.

Low density lipoproteins (LDL) are a form of cholesterol susceptable to oxidation, as up to half the fatty acids are polyunsaturated^[151] which are more susceptable to oxidation. Oxidation of LDL triggers changes in its structure that make it more conducive to form plaque in arteries.^[152] The oxidation of LDL plays a pathological role in cardiovascular disease pertaining to atherosclerosis, and supplements which reduce the oxidation of LDL (such as olive leaf extract) are thought to be protective. Due to the oxidized portions being fatty acids and vitamin E reducing lipid peroxidation, it is thought that vitamin E (and other chain breaking fat soluble antioxidants) play a particularly protective role.^[151][153] Vitamin E is also inherently present in LDL particules as the predominant antioxidant.^[151]

Oral supplementation of high dose vitamin E as α-tocopherol (1,000 IU) has been noted to increase the α-tocopherol content of LDL particules in type I diabetics by 127%.^[154]

Vitamin E is known to comprise a portion of LDL particulates, and is thought to serve to reduce lipid peroxidation of the LDL (which is theoretically an anti-atherogenic action). High doses of vitamin E supplementation appear to increase levels of vitamin E in LDL.

Homocysteine is an independent biomarker for cardiovascular disease risk particular to atherosclerosis,^[155] and due to a preliminary study in arthritic rats where supplemental vitamin E reduced homocysteine^[156] and the mechanism of homocysteine being oxidative^[157] the potential protective effects of vitamin E have been investigated further.

A study in hyperlipidemic smokers assessing homocysteine concentrations did not find relations with dietary vitamin E intake^[158] and vitamin E supplementation in otherwise healthy athletes did not influence homocysteine concentrations.^[159]

Despite preliminary evidence in rodents, supplementation of vitamin E does not appear to significantly reduce homocysteine concentrations.

Epidemiological research has revealed a correlation between sufficient vitamin E intakes and a reduced risk of heart disease,^[160][161] which may be related to either reduced LDL oxidation (and thus atherogenic formation) or from an increase in prostacyclin concentrations (antiatherosclerotic as well as vasorelaxants).^[27][28]

When looking at interventions using vitamin E (most alongside vitamin C), supplementation of antioxidant therapy has twice shown no significant effect with 400IU (given alone)^[162] and 800IU (confounded with vitamin C)^[163] with one study showing the positive effect of slowing carotid artery thickening in hyperlipidemic patients using a lower dose of 136IU vitamin E (coadministered with 250mg vitamin C, which may act a a confounder) over six years reducing atherosclerotic progression 25%.^[164]

Although epidemiological evidence exists suggesting a that sufficient vitamin E intake may protect against cardiovascular disease, the clincal trials examining these effects mostly find little benefit, except in trials in which confounders exist.

The augmentation index (thought to reflect arterial stiffness) appears to be improved by 5.3% in otherwise healthy males given 160mg of mixed tocotrienols daily for two months, although lower (80mg) and higher (320mg) doses were not effective.^[165]

When looking at diabetics, high dose vitamin E as α-tocpherol (1,600 IU) has failed to improve blood flow after eight weeks of supplementation relative to placebo^[166] and has been implicated in worsening blood flow mildly when continued at this dose for one year.^[149]

A study in otherwise healthy young males given tocotrienol supplementation at one of three doses (80, 160, or 320mg) daily for two months noted that the two higher doses were associated with mild reductions in aortic systolic blood pressure of around 5%.^[165]

Unlike red and white blood cells which experienced a peak concentration and subsequent plateau of vitamin E concentrations after four weeks of supplementation,^[93] platelets appears to require a full twelve weeks to reach maximal concentrations.^[93]

Vitamin E has been noted to inhibit platelet aggregation in vitro,^[71][72] leading to both its investigation into protecting against thrombosis (clots leading to heart attacks) but also to concerns over excessive bleeding when overdosed or paired with other anticoagulants.^[167]

The decrease in platelet aggregation may occur independent of any changes in lipid peroxidation in serum,^[168] and instead may be related to nitric oxide (NO) release (NO inherently inhibits platelet aggregation^[169]) due in part to suppressing superoxide release. This suppression of superoxide also does not appear to be related to vitamin E's antioxidant actions;^[71] although superoxide (a radical) can sequester NO leading to less NO activity and thus platelet aggregation,^[170][171] it appears that α-tocopherol does not work via this mechanism. Instead, it inhibits phosphokinsase C (PKC) in platelets.^[71][72] PKC-dependent phosphorylation of the enzyme which makes NO (eNOS) reduces its activity,^[172] and it appears that vitamin E attenuates this process at 500-1,000µM, leading to its inhibition of platelet aggregation.^[71]

This inhibition may be synergistic with alpha lipoic acid (ALA),^[168] which inherently has anti-platelet actions^[173] and can recycle vitamin E,^[174] potentially increasing its action.

Vitamin E (α-tocopherol) is able to inhibit PKC in platelets, which then leads to less platelet aggregation and is a mechanism not related to the antioxidant properties of vitamin E.

Intravenous infusions of vitamin E have been known to induce bleeding due to a lack of coagulation^[175] and this phenomena appears to be more pronounced in those with lower Vitamin K activity, such as those on warfarin therapy.^[176][167]

Studies which simply use oral vitamin E supplements (as α-tocopherol) daily have failed to notice any changes in bleeding times at doses from 600 IU for a month^[177] and up to 800IU (727mg) for four months.^[178]

A large scale study (Women's Health) assessing an average of 10.2 years usage of 600IU vitamin E every other day noted that, relative to placebo, the risk of venous thromboembolism was reduced significantly by 27%;^[179] this was particularly pronounced in the subjects who reported such an event previously (experiencing a 44% reduction) with minor protective effects (18%) in those without prior events.^[179] Such a benefit is thought to also apply to supplementation of γ-tocopherol (100mg) based on smaller trials.^[98]

While intravenous infusion of vitamin E significantly inhibits clotting, oral supplementation does not seem to have an effect on bleeding times. Nonetheless, oral supplementation seems to reduce the risk of venous thromboembolism in women, and γ-tocopherol may reduce thrombotic risk factors as well, although the evidence is weaker for this claim.

Supplementation of mixed antioxidants (including vitamin E) has been noted to attenuate the beneficial response of combination simvastatin and niacin therapy on HDL2 subfractions in people with coronary artery disease^[180][181] (HDL2 being a subfraction that is protective against CAD^[182]), although a study designed to test whether α-tocopherol was the causative agent in these trials by supplementing CAD patients on statins with 1,200 IU daily over the course of two years failed to find any effect of α-tocopherol on HDL2 or other HDL subclasses.^[183]

In regards to diabetic complications, vitamin E (α-tocopherol) has been noted to suppress the increase in diacylglycerol (DAG) concentrations induced by high glucose in vitro in a variety of cell lines including smooth muscle,^[74] aortic tissue,^[184] and in retinal tissue.^[185]

The release of DAG into a cell and the subsequent activation of phosphokinase C (PKC) plays a pathological role in cardiovascular complications seen in diabetes,^[186][187] and since vitamin E inhibits this pathway, it is theoretically possible that it would exert protective effects against diabetic complications.^[188]

Vitamin E holds a theoretical benefit in complications of diabetes secondary to reducing PKC activity, which mediates the effects of hyperglycemia a on a cell.

In studies assessing HbA1c levels in serum (a biomarker of long-term glucose levels), vitamin E has failed to significantly reduce glycation relative to placebo in diabetic patients.^{[149][189][190]}

Interventions have failed to find a protective effect of vitamin E supplementation on the glycation of HbA1c, a longer-term measure of blood glucose levels.

Although oxidative stress is associated with the development of impaired pancreatic β-cell function^[191] and overall pathogenesis of type II diabetes,^[192] and the fact that oxidative stress can trigger diabetes in rats,^[193] one large scale study (n=38,716) using 600 IU α-tocopherol every other day for ten years in otherwise healthy women failed to show a protective effect of vitamin E supplementation relative to placebo on the development of type II diabetes.^[194] Another study involving women with or at risk of cardiovascular disease also concluded that 600 IU vitamin over an average follow-up of 9.2 years had no effect on the development of diabetes.^[195] Serum α-tocopherol have at times,^[196][197] but not always,^[198][199] been associated with protective effects from the development of type II diabetes.

Vitamin E supplementation does not protect against the development of diabetes in either healthy women or those with or at high risk of cardiovascular disease.

Supplementation of 1,200 IU α-tocopherol daily for four weeks in type II diabetics prior to an oral glucose tolerance test noted that while DNA damage was not per se affected by supplementation that the increase seen after a glucose test (expected in type II diabetics^[200]) was exacerbated (13.6%) relative to placebo.^[201] The lack of changes without glucose test has been noted previously in type II diabetics with 400 IU over four weeks.^[202]

Elsewhere, supplementation of 500mg vitamin E (as either α-tocopherol or mixed tocopherols) appeared to mildly reduce oxidation in type II diabetics as assessed by serum F₂-Isoprostane levels although red blood cell antioxidants were unaffected.^[189]

1,800 IU of α-tocopherol daily for a year in diabetics noted that, relative to placebo, vitamin E appeared to worsen blood pressure and blood flow (flow mediated vasodilation) mildly at six months with a rather large increase in systolic blood pressure seen after one year in vitamin E (12.1mmHg) relative to placebo (2.1mmHg);^[149] this study also failed to find benefits on other parameters such as HbA1c and cholesterol with vitamin E.^[149] This particular study pooled type I and type II diabetics together, which may have differing responses to antioxidant therapy from Vitamin C and E favoring type I.^[203][154] Other studies on vitamin E in type II diabetics have failed to find protective effects (1,600 IU for eight weeks),^[166] or any change in glucose levels or β-cell function over 2 months at a dosage of 800mg, although triglyceride levels were significantly reduced.^[190]

Vitamin E supplementation has either no effect or slightly negative effects on glucose levels and various cardiovascular risk factors in type II diabetics, with one measure oxidation and triglyceride levels being the only minor exceptions.

Interleukin-6 (IL-6) is normally produced during exercise from contracting skeletal muscle^[204][205] where it is released into serum^[206] where it is thought to positively influence muscle protein synthesis.^[207] One mechanism by which IL-6 may be released is through oxidative stress, since exercise causes oxidative stress within muscle tissue,^[208] which can lead to the production of IL-6.^[209] Since vitamin E is an antioxidant, it is possible that it may attenuate IL-6 production, and in fact this effect has been demonstrated with the antioxidant N-acetylcysteine^[210] as well as an antioxidant cocktail including vitamin E.^[211]

Oral supplementation with antioxidants (400IU α-tocopherol plus 500mg Vitamin C) for one month prior to resistance training prevented both an increase in lipid peroxidation from exercise and the exercise-induced increase in IL-6 and IL-1ra concentrations.^[212] The actual mRNA transcription rates for IL-6 in skeletal muscle and its accumulation within the tissue are unaffected by antioxidant therapy, suggesting that the mechanism of action was to prevent the release of IL-6 from skeletal muscle.^[212]

Oxidative stress appears to be involved in the production and release of interleukin six (IL-6) from skeletal muscle into the blood during exercise, and antioxidants can attenuate or abolish the release of IL-6. Vitamin E has been shown to be capable of suppressing IL-6 release from muscle into serum when paired with vitamin C.

Vitamin E deficiency within skeletal muscle results in the same mitochondrial dysfunction and increased lipid peroxidation as in other cells, although they are more susceptable to such damage relative to liver cells.^[213] These results suggest a mechanism for the observed myopathies that occur in instances of vitamin E deficiency^[214][215] which appear to fully deplete the vitamin E content of skeletal muscle^[215] and may promote said muscle tissue to greater damage from exercise.^[216]

A deficiency of vitamin E results in skeletal myopathies associated with damage and prooxidative changes to the mitochondria.

Supplementation of 800IU (α-tocopherol) to elite athletes for two months prior to an Ironman race failed to improve performance relative to placebo therapy^[159] and in elite cyclists given supplementation for five months did not lead to improved aerobic performance.^[217] These two studies in elite athletes differ in their observations on lipid peroxidation despite similar inefficacy on performance, as one study noted a reduction in concentrations of malondialdehyde (an oxidative degredation product of polyunsaturated fatty acids)in the supplemented group^[217] whereas the other noted no significant changes immediately after exercise, but did see an increase in lipid hydroperoxides 90 minutes afterwards.^[159]

Regardless of its efficacy in modulating oxidation in the athlete, supplementation of vitamin E does not appear to be able to improve prolonged aerobic exercise performance relative to placebo.

In a study where 11 healthy men took 400 IU vitamin E once daily along with 500 mg of vitamin C twice daily for 4 weeks before being subject to strenuous aerobic exercise, the VO₂peak of the vitamin group did not differ from placebo, nor did the rate of perceived exertion or maximal power output. The vitamin group also had lower superoxide dismutase activity in their muscles versus the placebo group as measured through a muscle biopsy. However, markers of oxidative stress in the muscle biopsy was ultimately unaffected.^[7]

Rheumatoid arthritis is a disease state in which oxidative radicals (particularly those from lipid peroxidation) have been noted to be elevated both in serum^[218] as well as the synovial fluid central.^[219][220] Since α-tocopherol concentrations in the synovial fluid of people with rheumatoid arthritis are lower than normal,^[221][222] the effects of supplemental α-tocopherol have been investigated.

In an analysis of the Women's Health Study, supplementation of 600IU of vitamin E (α-tocopherol) daily over an average ten years failed to exert protective effects against the development of rheumatoid arthritis.^[223]

Supplementation of vitamin E as α-tocopherol does not appear to reduce the risk of developing rheumatoid arthritis relative to placebo in women.

The progression of osteoporosis and age-related bone loss is known to be associated with oxidative stress,^[224] leading some researchers to investigate the role of vitamin E in bone metabolism.

It has been noted that an oral intake of 600mg/kg vitamin E (as α-tocopherol) has stimulated bone loss in rodents secondary to increasing activity of osteoclasts,^[225] although that is approximately 30-fold the recommended dose for rodents.^[226] This interference may be related to such high doses interfering with the activity of Vitamin D, which has been noted with high doses in broiler chicks.^[227]

Conversely, beneficial effects on bone structure have been noted in otherwise healthy male rats at an oral intake of 60mg daily (with more efficacy seen with γ-tocotrienol than α-tocopherol,^[69]) as well as in ovarectomized rats subject to bone fracture, where α-tocopherol showed anabolic properties on bone tissue at this same dose.^[228][229]

In rodent studies, supplementation of low doses of vitamin E appear to confer anabolic properties to bone tissue, whereas superloading vitamin E to high levels appears to stimulate bone tissue losses.

In assessing dietary and serum α-tocopherol in older subjects, it was noted in men that over a 12 year period the lower four quintiles of vitamin E intake had a greater risk of overall fractures (Hazard ratio of 1.84, 95% confidence interval of 1.18-2.88); a similar result was found with women over a 19-year followup (Hazard ratio of 1.20, 95% confidence interval of 1.14-1.28).^[230] Supplementation of vitamin E as α-tocopherol appeared protective in women against any fracture (HR 0.86; 95% CI of 0.78-0.94), and it appeared that vitamin E intake positively correlated with lean mass and bone mineral density (BMD) in women.^[230] It was noted by the authors that intakes above 10mg did not appear to cause dose-dependent resistance to fractures, and that a near-exponential increase in fractures at intakes below 5mg may have explained much of the protective effect.^[230]

Other correlational studies have noted lower vitamin E levels in the serum of hip fracture patients relative to control at the time of hip fracture^[231] and higher vitamin E levels in serum (both α-tocopherol and γ-tocopherol) to be correlated with better functioning after hip fracture.^[232] Despite a positive correlation being noted previously between BMD and vitamin E intake, it was in a study with an average intake of 5mg daily;^[230] another study with an average intake of 39mg daily failed to find such an association.^[233]

When looking at epidemiological research (surveys and correlations), it seems that a better vitamin E status and vitamin E supplementation are both protective factors against fractures in the elderly. This may be potentially explained by a large increase in fracture risk when vitamin E intake drops below 5mg daily (7.5 IU, 33% of the recommended daily intake). Dose-dependent protective effects do not appear to exist above 10mg daily.

α-tocopherol increases lymphocytes proliferation (to a degree more than other vitamers) in aged mice.^[234][235]

It has been noted that the increase seen in Peripheral Blood Mononuclear Cell (PMBC) proliferation (induced ex vivo) following ingestion of 200mg α-tocopherol in elderly people is lessened when ingested alongside 2.5g of EPA+DHA (fish oil) supplementation.^[9]

α-tocopherol has been noted to decrease IFN-γ concentrations at the 50-100mg dosage range after six months supplementation in otherwise healthy older persons.^[236]

When tested in vitro, vitamin E (α-tocopherol) has been noted to increase proliferation and IL-2 secretion from a variety of immune cells including splenocytes (where proliferation, but not IL-2 secretion, was affected),^[235] purified T-cells,^[76] and naive T-cells,^[237] yet not memory T-cells.^[237]

Supplementation of 50mg and 100mg of α-tocopherol daily for six months in otherwise healthy older adults has been noted to increase circulating IL-4 concentrations with at trend towards increasing IL-2.^[236] As IL-2 tends to be an inflammatory (Th1) cytokine and IL-4 an antiinflammatory (Th2), this change may be seen as proinflammatory although due to shifts towards Th2 during aging,^[238][239] it is thought to also be immunosupportive for elderly patients. In accordance with this hypothesis it has been noted that the dampening effects of fish oil on vitamin E's enhancement of delayed-type hypersensitivity (DTH) was seen alongside no IL-2 secretion from lymphocytes in people given both supplements when tested ex vivo.^[9] An increase in IL-4 is not observed in otherwise healthy youth given supplementation at 200mg (as either pure α-tocopherol or mixed tocotrienols)^[240] except perhaps in the context of vaccine augmentation.^[241]

Vitamin E has been noted to reduce PGE₂ secretion from macrophages isolated from aged mice,^[76] which is important since the increase of PGE₂, which suppresses IL-2 production, from the macrophages of old mice is a factor underlying reduced T-cell-mediated immunity (PGE₂ suppresses IL-2 production^[242]) seen during the aging process (as macrophages can influence T-cell function secondary to secreting prostaglandins^[76][243]).

Supplementation of vitamin E as either α-tocopherol or as mixed vitamers (mostly α-tocopherol and γ-tocopherol) at 500mg for eight weeks altered the vitamin E content of neutrophils, with the changes paralleling those found in serum (a decrease in γ-tocopherol seen with supplementation of α-tocopherol only, an increase in both seen with mixed tocopherols).^[189]

Supplementation of various doses of vitamin E (60, 200, and 800 IU) for four months in otherwise healthy aged adults failed to significantly modify the response of neutrophils in vitro against Candida albicans.^[178]

One study has noted that supplementation of γ-tocopherol (315mg) alongside α-tocopherol (75mg) for eight weeks, but not 500mg of α-tocopherol alone, was able to reduce serum levels of leukotriene B4 by 17% relative to baseline in type 2 diabetics;^[189] leukotriene B4 being a neutrophil-derived, arachidonic acid-based eicosanoid involved in atherosclerosis.^[244] This has been noted previously in rats^[245] and although both vitamers seem effective in vitro in suppressing leukotriene B4 secretion γ-tocopherol seems more potent (effective at 25μM compared to 50μM with α-tocopherol).^[189]

When comparing aged mice fed either normal (30ppm) or high doses (500ppm; thought to be approximate to 500mg in a human) vitamin E as either α-tocopherol or γ-tocopherol for four weeks and stimulating their T-cells ex vivo (with anti-CD3/CD28), supplementation showed influence on T-cell function in a dose-dependent manner with differences depending on the form used.^[246] Notable genes influenced included the CD40 ligand (10-fold induction), leukemia inhibitory factor (3.3-fold induction), and Slamf1 (4.4-fold induction) with high-dose α-tocopherol, whereas SLC25A30 (also known as UCP6,^[247] induced 10.4-fold) and polovirus receptor related 2 (10.8-fold) were most heavily affected by γ-tocopherol (low dose relative to α-tocopherol); many other genes were influenced to lesser degrees.^[246]

Vitamin E is known to stimulate T-cell proliferation in vitro, and the actions may differ depending on the particular vitamer used.

Age is known to be associated a reduction in immune responsiveness^[248] with particular regard to T-cell functions of which include delayed responses to mitogens, antibody responses to immunization with antigens, and reductions in delayed-type hypersensitivity (DTH) and IL-2 production.^[249][250]

When tested in otherwise healthy elderly persons, 50mg and 100mg of α-tocopherol for six months, immune responsiveness (as assessed by DTH reactivity) has been noted to be increased, with more drastic increases in subjects with low baseline DTH reactivity.^[236] Other studies have noted this benefit occurring with α-tocopherol supplementation on this parameter in otherwise healthy elderly persons with 200mg,^[94][251] and due to 50mg working in only those with low baseline DTH reactivity^[236] it is thought that the doses required for a response inversely relate to initial susceptability.

It has also been noted that coingestion of fish oil supplementation (5g total, containing 2.5g EPA+DHA) alongside vitamin E (100, 200, and 400mg) lessened the T-cell-mediated immunoenhancing properties of vitamin E.^[9] Limited studies assessing T-cell function in non-elderly adults (20-50yrs) given supplemental vitamin E have not found any significant influence.^[240]

At least in the elderly, who may have compromised immune function related to impaired T-cell function, supplemental vitamin E at low doses appears to enhance immune function.

RBL-2H3 mast cells incubated with α-tocopherol (100µM) as well as β-tocopherol appear to enhance basal and stimulated degranulation of mast cells, while neither α-tocopherol phosphate (a biologically relevant form of α-tocopherol^[252]) nor Trolox (water soluble variant of vitamin E) do.^[253] Tocotrienols from rice bran (mostly γ-tocotrienol), however, have been noted to have suppressive effects on degranulation in mast cells up to 50µM, although all tocotrienols appear to have suppressive effects.^[108] These results support the view that the 6-OH position of the backbone and the sidechain are both relevant to the specific actions of select tocopherols.^[253]

α-tocopherol has been noted to be involved in promoting mRNA involved in vesicular transport in mice after three months feeding,^[254] although the mast cell proteins do not appear to be induced in vitro over the course of 24 hours from α-tocopherol at the concentration at which it causes degranulation.^[253]

When looking at in vitro studies, it appears that α-tocopherol may stimulate mast cell degranulation (a pro-allergenic effect) whereas the tocotrienols may have the opposite effect and suppress degranulation.

Rice bran tocotrienols (which consist mostly of γ-tocotrienol) fed to mice at 1mg/kg daily for one week appear to confer anti-allergic effects against skin sensitization by reducing symptoms 50% relative to control, which may reflect the suppression of degranulation at the level of the mast cell, as serum histamine was decreased, yet IgE (released from T-cells to induce degranulation^[255]) was not affected by supplementation.^[108]

It has been noted in epidemiological research that higher vitamin E intake is associated with less risk of asthma in women^[256] and in asthmatics there are reduced activity of antioxidant system in the lung including those related to vitamin E.^[257][258]

Supplementation of 500mg vitamin E (α-tocopherol) for six weeks in nonsmoking asthmatics on corticosteroids noted that supplementation, relative to placebo, was associated with a mild improvment in responsiveness to methacholine yet had no influence on other measured parameters (FEV1, FVC, morning peak flow, and bronchodilator use) or subjective symptoms.^[259]

While there is evidence to suggest that asthmatics may be undergo higher oxidative stress in their lungs, supplementation of vitamin E does not seem to affect most of the signs or symptoms of asthma.

There is evidence that vitamin E supplementation boosts clinically relevant markers of immune function in the elderly exposed to vaccines.^[251] Partly based on this observation, elderly people taking minor micronutrient supplementation and adminstered an influenza vaccine were randomized to an additional 200 IU vitamin E (α-tocopherol) or placebo supplementation over the course of one year, resulting in reduced upper respiratory tract infections (URTIs) from a 64% occurrence to 50%, most of which were attributable to the common cold (which comprises 84% of URTIs).^[260]

Animals subject to immunization show an increased immune response to tetanus vaccinations^[261] and influenza vaccines^[262] when vitamin E is coadministered with the vaccines. Vitamin E co-administration is associated with greater IFNγ concentrations in serum in these contexts^[261][262] which is thought to underlie the benefits, as IFNγ is secreted from T-cells and natural killer cells in response to infection,^[263] exerting antiviral properties.^[264] Increased IL-4 secretion and suppressed IL-6 have also been noted in humans supplementing vitamin E with vaccines.^[241]

Vitamin E (multiple vitamers) may increase the immune response to vaccinations and ultimately the production of antibodies to the vaccine, serving an adjuvant role.

A study assessing vitamin E status of otherwise healthy older adults found that serum vitamin E in non-deficient persons (and who were not taking vitamin E supplements) was not associated with the serological response to vaccination for influenza.^[265]

Interventions with supplemental vitamin E have found an increased response to vaccination against hepatitis B associated with supplementation of 200mg vitamin E (α-tocopherol) before vaccination, with a 6-fold increase in antibody titre which outperformed both 60mg and 800mg of vitamin E (each reaching 3-fold).^[251] Increases in the response to tetanus have been noted in young and otherwise healthy adults subject to vaccination paired with 400mg (70% tocotrienols,^[241] which based on animal evidence may be more effective than α-tocopherol^[261]).

Although baseline vitamin E levels do not appear to be correlated with antibody production to vaccines, studies using moderate supplemental dosages of vitamin E (200-400mg range) show an adjuvant role when compared to placebo in both young and elderly individuals.

Vitamin E dietary deficiency in the rat has been noted to increase corticosterone concentrations both at rest and after anxiety testing, with the largest difference seen in adult rats after testing where corticosterone concentrations were near doubled in vitamin E-deficient rats relative to controls.^[146] It has also been noted in cattle and buffalo that vitamin E administration in the diet (along with selenium) was able to reduce cortisol concentrations^{[266][267][268]} although when tested in vitro in bovine adrenal cells, vitamin E (in combination with Vitamin C) failed to influence cortisol secretion either alone or in the presence of ACTH stimulation.^[269]

In humans, vitamin E (400IU as α-tocopherol) used alongside Vitamin C (1,000mg) in the context of physical exercise for four weeks appeared to attenuate the 170% increase in post-exercise cortisol down to 120%.^[270] Such an effect has been noted with vitamin C supplementation in isolation, and studies using only α-tocopherol have failed to find any effect of supplementation on cortisol.^[159]

Vitamin E supplementation can reduce cortisol levels in bovids, and a deficiency of vitamin E appears to increase cortisol in rats. Despite these animal data, however, studies on vitamin E supplementation in humans have not shown any benefit relative to placebo.

Supplemental vitamin E at 300mg daily in uremic patients, who tend to have elevated prolactin concentrations due to reduced clearance,^[271][272] has been noted to reduce circulating prolactin (from 50.8ng/mL down to 15.4ng/mL) without apparent influence on free testosterone.^[273] There are currently no studies investigating the effect of vitamin E supplementation on prolactin levels in healthy humans, however.

At least one study has noted reductions in prolactin in uremic patients supplemented with vitamin E, although there is no evidence concerning healthy people at this time.

Supplementation of 800mg vitamin E (α-tocopherol) daily for a month in otherwise healthy elderly people has failed to significantly modify circulating T3, T4 (free or total) or the uptake ratio of T3 relative to placebo.^[274] Four weeks of 800mg α-tocopherol in young males and females not on contraceptives, however, has led to a slight decrease in thyroid hormones (T3 by 26.3-31% and T4 by 12.3-14.6%).^[177] Two studies done over longer periods of time have failed to find alterations in thyroid function, however: one study done over an average of 3 years with 100-800 IU/day in ages ranging from 24-62 years (mean 28 years),^[275] and one over 12 weeks using 900IU daily in healthy college students.^[93]

Vitamin E has the ability to act as a chain-breaking anti-lipid peroxidation agent^[12], specifically in lipoproteins where it is incorporated by the liver.^[276] 'Chain-breaking' refers to being able to interrupt a series of oxidative events caused initially by oxidants.^[57][277] Vitamin E appears to be the central chain-breaker, as it still retains this ability even during deficiency states.^[278]

Supplemental vitamin E (as alpha-tocopherol) can alleviate mitochondrial dysfunction that is secondary to vitamin E losses in rats.^[279]

In humans, supplementation of 400-800 IU of vitamin E in those with artherosclerotic buildup (artery plaque) was associated with a greatly reduced chance of a cardiac event occurring.^[280] A possible mechanism of action for these results may lie in vitamin E's reduction of levels of prothrombrotic factors.^[281][12]Doses of 300IU can improve markers of lipid peroxidaiton in people diagnosed with coronary spastic angina,^[282] which may also account for vitamin E's reduction of cardiac events.

Markers of in vivo LDL lipid peroxidation known as F2-isoprostanes^[283] that can be induced by vitamin E deficiency^[284] may subsequently be suppressed with vitamin E supplementation.^[285][281]

Vitamin E (α-tocopherol) is known to act counter to its usual role as an anti-oxidant when embedded in LDL particles in vitro, instead promoting oxidation^{[286][287][288]} which is a possible explanation for at times null effects in atherosclerosis.^[287]

This pro-oxidative effects seems to be mediated by α-tocopherol sequestering free radicals to a degree where itself turns pro-oxidative, which would then normally be reduced by co-antioxidants (such as Vitamin C); in the event a co-antioxidant cannot act on the newly formed α-tocopherol radical, the radical then in turns accelerates the lipid peroxidation it initially suppressed.^[289][290]

Nitrosylation (oxidation involving nitrogen) is known to be mediated in large by peroxynitrate (ONOO^-), the product of the superoxide radical (O₂^-) pairing with nitric oxide (NO).^[291] The peroxynitrate radical can oxidize unsaturated fatty acids^[292] and its production is accelerated in the cell membrane;^[293] although it can react with γ-tocopherol (forming 5-nitro-γ-tocopherol or NGT,^[294] thought to also extend to δ-tocopherol^[295]) it cannot act similarly against α-tocopherol or less importantly β-tocopherol which instead trap nitrogen radicals while still remaining chemically active.^[295] Furthermore, when incubated alongside L-tyrosine (which is usually a molecular target of nitrosylation^[296]) it seems that γ-tocopherol is preferred as a target for peroxynitrate.^[297] γ-tocopherol loses its antioxidative metabolism in this reaction (it does not get converted to CEHC as a metabolite).^[298]

There are elevated serum or urinary concentrations of NGT in some disease states such as cognitive decline^[299] and coronary artery disease,^[300] and Alzheimer's disease,^[299] where it also appears at higher levels in the brain tissue itself, specifically in areas where there is histopathological damage.^[301][302]

While all vitamers appear to have general antioxidant properties against nitrogen based radicals, γ-tocopherol has a unique role in effectively sequestering and reducing the oxidative effects of peroxynitrate. The metabolite of this reaction, NGT, is elevated in certain disease states, suggestng that this process is important in the pathology and implicates γ-tocopherol (and possibly γ-tocotrienol) in unique protective roles.

When 800IU α-tocopherol was given for two months prior to an Ironman marathon, supplementation was ineffective in modifying lipid hydroperoxides in serum before or immediately after the race; however, there was a large spike (indicative or more lipid peroxidation) seen after 90 minutes relative to placebo, alongside an increase in F₂-isoprostanes^[159] (oxidative product made from lipid peroxidation^[303]).

Supplementation of 1,200 IU α-tocopherol daily for four weeks in type II diabetics exacerbated the oxidative DNA damage done following an oral glucose tolerance test by 13.6% relative to placebo (with no difference in damage seen before the glucose tolerance test was administered).^[201] Such an increase in DNA damage has not been noted with 400 IU in type II diabetics not administered a glucose tolerance test, however.^[202]

Rectal administration of vitamin E (8,000 IU) in people with ulcerative colitis daily for twelve weeks appeared to be able to slightly reduce disease severity, with all patients reporting some benefit and 9 (out of 15) reporting remission and maintenance of therapy over the course of eight months being associated with no flare-ups.^[304]

Rectal administration of high doses of vitamin E may help reduce symptoms in people with ulcerative colitis.

Non-alcoholic fatty liver disease (NAFLD) is a disease state associated with oxidative stress^[305] and characterized by an increase in triglyceride and fatty acid accumulation in liver tissue leading to scarring,^[306] and is known to be associated with less circulating antioxidants in serum (including α-tocopherol^[307]) and oxidative byproducts.^[308][309] Vitamin E is thought to play a therapeutic role in treating NAFLD due to its antioxidant properties.^[310]

Nonalcoholic fatty liver disease (NAFLD, also known as nonalcoholic steatohepatitis or NASH) is a condition associated with elevated oxidative stress. Since vitamin E being an antioxidant, it has been investigated for its role in reducing symptoms of NAFLD/NASH.

Pilot studies on the topic of vitamin E and NAFLD have noted benefits to serum biochemical markers such as transforming growth factor β1 (TGF-β1, which contributes to liver fibrosis)^[311] and the liver enzyme alanine aminotransferase (ALT),^{[312][311][313]} at times being noted even if fibrotic and steatohepatitis scores in the liver did not significantly change.^[311][313] At least two studies have noted benefits to fibrotic scores, however, although one was a retrospective study of vitamin E at 300mg for periods longer than two years^[314] whereas the other also used vitamin C alongside vitamin E at 1,000mg and 1,000IU respectively.^[2] Since one pilot study has noted benefit to fibrosis in people with steatohepatitis (inflammation) but not those in NAFLD without inflammation, it is thought that vitamin E may prevent fibrosis by affecting inflammation in the liver.^[311]

The currently most well-conducted trial examining vitamin E's effect on NAFLD used 800IU vitamin E (α-tocopherol) as a daily supplement for 96 weeks, which led to a greater rate of improvement on histology and serum liver enzymes relative to placebo, with 43% of subjects seeing benefit versus 19% in the placebo group^[315] with the benefits of vitamin E being additive to weight loss^[313] (which also has therapeutic effects on NAFLD)^[316]) although serum ALT rises again when vitamin E is ceased for 24 weeks.^[313]

At least one study which used vitamin E (600IU) alongside vitamin C (500mg) for one year in obese children who were also subject to weight loss noted that the benefits of weight loss on insulin sensitivity and liver enzymes washed out the benefits of antioxidant therapy.^[1]

Supplementation of high dose vitamin E in persons with NAFLD appears to be more effective than placebo at reducing elevated serum enzymes and some other factors indicative of liver damage, although evidence is mixed on whether vitamin E actually reduces fat buildup in the liver and the subsequent fibrotic score (may only occur in persons with evidence of inflammatory damage to the liver, and not as a per se benefit).

Vitamin E has, at times, been either noted to have lower circulating levels in the plasma of smokers^[317][318] or no significant difference relative to nonsmokers;^[319][320] an increased clearance from the blood does seem apparent though,^[321][322] thought to be due to vitamin E being degraded when exposed to components of cigarette smoke.^[323] This depletion rate seems to be lesser when Vitamin C levels in serum are higher,^[322] and supplementation of vitamin C (500mg twice daily) can attenuate the rate of increased α-tocopherol depletion from plasma by a quarter while also reducing the increased γ-tocopherol clearance by 45%^[321] (although γ-tocopherol does not tend to be depleted abnormally in smokers relative to nonsmokers, if not elevated^[320]).

It has also been noted that the increased clearance of both α-tocopherol and γ-tocopherol from plasma is not due to metabolism through the cytochrome P450 pathway, since α-carboxyethyl-hydroxychroman (CEHC) and γ-CEHC plasma levels (respectively) are not increased.^[321][116] The mechanism of clearance of these vitamers may instead be due to nitrogen radicals in cigarette smoke forming 5-nitro-γ-tocopherol (NGT) when reacting with γ-tocopherol^[294][295] although this process cannot occur with α-tocopherol.^[294] An increase in urinary NGT has been confirmed with smoke exposure, however.^[324] In regards to α-tocopherol, its elimination seem to operate through oxidative pathways, but the details are not yet known.^[116]

Due to the increased rate of clearance, smokers are thought to have higher requirements for α-tocopherol, although the degree of which is uncertain.^[325]

Cigarette smoking appears to increase the rate of α-tocopherol elimination from the blood, a reaction that appears to be slowed when other antioxidants such as vitamin C are also supplemented. This likely means an increased requirement for vitamin E or other antioxidants in smokers, although the degree of increase is not currently known.

The pathological changes that occur with cataract formation are known to be oxidative, and application of antioxidants exert a protective effect against cataracts in vitro.^[326][327] Of the three variants of cataract formation (nuclear, corticol, and posterior subcapsular cataracts), different oxidative stressors may influence pathology (e.g. smoking and H₂O₂ promoting nuclear cataracts^[326][328] and corticosteroids promoting posterior subcapsular cataract formation^[329][330]). Due to the benefits seen in mixed antioxidant supplementation, including vitamin E, on macular degeneration (which may also have an oxidative pathogenesis),^[331] as well as general protective correlations with dietary vitamin E and cataract formation,^[332] the role of supplemental vitamin E in isolation has been tested.

Supplementation of vitamin E (as 500 IU α-tocopherol) to older people with either early or no signs of cataract formation over the course of four years yielded a cumulative incidence of forming cataracts of 4.5%, which was not significantly different than placebo (4.8%); subgroup analysis based on type of cataract( posterior subcapsular cataract or nuclear cataract) also showed no statistically significant effect.^[333] Incidences of early or late cataract formation also did not differ between groups.^[8]

Previous studies have found benefits with mixed nutrient supplementation and zinc in isolation on cataract formation,^[331] but trials assessing solely the combination of vitamin E and Vitamin C have failed to find a protective effect^[334][335] suggesting efficacy lays either with zinc or some efficacy seen with β-carotene (routinely included in these formulations) in smokers exclusively.^[336][337]

Although mixed antioxidant supplements appear to have protective effects against cataract formation, this may be due to nutrients such as zinc which have shown benefits in isolation. When used by itself, vitamin E has failed to show any protective effects on either the risk of developing cataracts or their continued formation.

The administration of vitamin E (intravenous at 100mg/kg) in rabbits has been noted to improve the levels of antioxidative biomarkers (glutathione, MDA) relative to control, and when coadministered alongside testosterone it was able to prevent a decline in these biomarkers normally seen with testosterone alone.^[338]

There is a small decrease in some cancer risk with daily supplementation of vitamin E (as alpha-tocopherol) according to some large-scale epidemiological studies.^[339][340]

One study that assigned aspirin (100mg) to be taken every other day for ten years and then assigned on the alternating days either vitamin E (600 IU) or placebo found that vitamin E was not associated with any protective effects on cancer mortality (breast, lung, and colon).^[143]

One cohort study in China using a sample of 132,837 people found that during follow-up that 267 people (0.2%) developed cancer of the liver.^[341] In comparing vitamin E ingestion from the base sample against the cohort that developed liver cancer, intake of vitamin E supplements was inversely related to cancer occurrence with a hazard ratio of 0.52 (almost half the risk) and a 95% confidence interval of 0.3-0.9, and dietary vitamin E intake was also inversely related to cancer development.^[341]

When looking at epidemiological evidence, dietary vitamin E intake had a minor protective effect on prostate cancer in some studies ^[342][343] but not in others,^[344][345] while serum levels of α-tocopherol are either weakly associated^[346] or not associated^[347] with increased risk although γ-tocopherol levels were inversely associated with risk.^[346]

In assessing the data from the ATBC trial (studying the effects of vitamin E and β-carotene on lung cancer in smokers,^[348]) where there were protective correlations of borderline statistical significance with both α-tocopherol and γ-tocopherol levels in serum,^[349] it was noted that supplementation of 50mg α-tocopherol was associated with a 32% reduction in prostate cancer risk and a 41% reduction in prostate cancer mortality in smokers.^[350] When following up on this study 20 years after its initiation (1985-1988), it was noted that while dietary vitamin E was not related to prostate cancer, the highest quintile of serum γ-tocopherol was associated with a protective effect against advanced prostate cancer (RR of 0.50; 95% CI of 0.30-0.84) similar to baseline α-tocopherol (RR of 0.56; 95% CI of 0.36-0.85) and appeared to be slightly more protective with supplementation of 50mg α-tocopherol relative to placebo.^[351] There did not appear to be a protective effect of α-tocopherol that manifested during the initial trial period; it was instead evident six years post-intervention.^[351]

It has also been noted that among smokers, who have higher instances of prostate cancer associated with smoking,^[352] risk is associated in those with low α-tocopherol concentrations in serum.^[353] Statistically nonsignificant trends indicate that this correlation may extend to advanced prostate cancers and γ-tocopherol.^[354]

It appears that higher serum vitamin E levels at baseline (before prostate cancer is diagnosed) and vitamin E intake may be associated with less instances of advanced prostate cancer and reductions in prostate cancer-related mortality in smokers. Observational studies investigating the association of vitamin E and prostate cancer (and not limited to advanced cases) seem to be on the fence about a minor protective effect or none at all.

A major clincial trial involving vitamin E supplementation either alone at 400IU or in combination with 200µg selenium showed that supplementation did not protect against prostate cancer development in men over 50 when supplemented over the course of 12 years (instead trending towards an increase; a subgroup analysis of smokers also did not find any effect).^[355] A later analysis of the same trial (SELECT) found that vitamin E supplementation was associated with a slight but significant increase in the risk of prostate cancer with a hazard ratio (HR) of 1.17 (99% CI of 1.004-1.36).^[356] This risk is much higher in those with low selinium status (a 63% increased risk when supplemented with vitamin E in patients in the 40th percentile of toenail selinium levels), and the risk for high-grade cancers correlated with vitamin E supplementation is also higher in this population.^[357] However, selenium coingestion (200µg) may mitigate the increased risk due to vitamin E supplementation, since in the first analysis the nonsignificant trend of vitamin E was not present with the combination^[355] and the estimated increase in risk with vitamin E in the second analysis was lessened from 1.6 people (per 1000) down to 0.4 in combination.^[356]

While mild, there is an increase in prostate cancer risk of otherwise healthy men (when smoking is not controlled for) associated with supplementation of α-tocopherol at the dosage of 400 IU.

Recent evidence suggests that antioxidants may have the ability to promote certain types of cancer in people who are already at higher risk, such as smokers. Genomic analysis of lung cancers has revealed a disproportionate amount of mutations in genes that activate the endogenous antioxidant program, suggesting that reducing reactive oxygen species could actually promote carcinogenesis.^[358][359] Moreover, studies have shown that certain oncogenes (genes associated with a cancer-promoting effect when dysregulated) promote tumorigenesis in part by activating the NRF2-mediated endogenous antioxidant program.^[360][361]

It has recently come to light that certain cancers including lung cancer may exploit endogenous antioxidant defense mechanisms to reduce ROS-dependent activation of p53, a key tumor-suppressor.

A recent study by Swiss research group noted that antioxidants may have a particularly detrimental effect on the development of lung cancer. When mice harboring mutations that increase their risk of lung cancer were treated with vitamin E, or the antioxidant acetylcysteine, early precancerous lesions developed at an accelerated pace, and the mice developed more tumors at advanced stages of disease.^[362] Although the antioxidants in this study reduced oxidative stress as would be expected, both vitamin E and actetylcysteine decreased the expression of p53, a key tumor suppressor protein. Although this work was performed in a mouse-model that is more susceptible to cancer than wild-type mice or humans, antioxidant-mediated suppression of p53 expression was confirmed in a human lung cancer cell line.^[362]

Supplementation with vitamin E or the antioxidant acetylcysteine accelerated carcinogenesis in a mouse model for lung cancer, as well as tumor cells by reducing expression of p53, a key tumor-suppressor protein. While this does not prove that antioxidants promote cancer in healthy mice or people, it does suggest that caution may be warranted in regards to antioxidant supplementation in high-risk populations, such as smokers.

A meta-analysis assessing 19 clinical trials using vitamin E supplementation for over one year in length (9 of which assessed vitamin E in isolation rather than in conjunction with other micronutrients) in the range of 19.5-2,000IU (median value of 400IU) noted that, relative to placebo treatment, there was no overall increase in mortality seen with vitamin E supplementation.^[363] This was thought to be due to differences in studies using doses of vitamin E below 400IU (which showed a nonsignificant protective effect against mortality) and doses above 400IU used in 11 trials which had a relative risk of 1.04 (95% CI of 1.01-1.07). Although when the use of concomitant multinutrient formulations alongside vitamin E was controlled for, the risk was slightly increased from 34 persons (per 10,000) to 63.^[363] The authors noted a limitation of this study was a lack of evidence in otherwise healthy aged adults, as two of the studies using vitamin E above 400IU (studying cataract formation^[331][333]) assessed healthy cohorts whereas the other nine^{[150][364][365][366][367][163][368][369][280]} were in diseased cohorts, and studies in healthy adults using less than 400IU were all confounded with other nutrients^[4][5][6]).

It was also noted that after initially controlling for dosage there wasn't a statistically significant reduction in mortality seen in the low dose vitamin E group (as the 0.98 relative risk ratio had a nonsignificant 95% CI of 0.96-1.01), but in secondary analyses there was a minor protective effect with low doses reaching 33 fewer deaths per 10,000 persons compared to placebo; a clinical relevance paralleling the 34/10,000 increase seen with high dose vitamin E supplements (prior to controlling for other nutrients).^[363]

A small but significant increase in all-cause mortality has been noted in at least one meta-analysis when Vitamin E was used at doses above 400IU. The meta-analysis was focused mostly on unhealthy persons (usually those at high risk for cardiovascular disease) and on α-tocopherol specifically. It is unclear if low doses of vitamin E confer a protective effect, but it cannot be ruled out. Whether these results apply to healthy cohorts is not known.

Because smokers are particularly at risk for increased mortality, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study^[348][370] was performed to assess the effects of vitamin E (and beta-carotene) supplementation in male smokers. Although initial analysis of the data from this study failed to show an effect of vitamin E on overall mortality,^[348] smoking is known to increase clearance of vitamin E from the plasma, which is normalized by supplementation with vitamin C.^[321] Moreover, vitamin E interacts with vitamin C in vitro as well as in vivo.^{[371][372][373][321]} 

This prompted a Swiss group in 2009 to re-examine the data from the ATBC study. After accounting for age and vitamin C intake, it was found that vitamin E increased mortality in individuals with a median vitamin C intake above 90mg/day aged 50-62 years by 19% (95% CI: 5, 35).^[374] In contrast, vitamin E decreased mortality in subjects aged 66-69 years by 41% (95% CI: -56, -21), and had no effect on participants in the study with a vitamin C intake below the median 90mg/day.^[374] Although it is difficult to extrapolate the results of this study in male smokers to the general, healthy population, this work suggests that the effects of vitamin E on all-cause mortality may be population-specific, and possibly influenced by the intake of other nutrients.

The effects of vitamin E supplementation on all-cause mortality may be population-specific, and influenced by the intake of other nutrients, particularly vitamin C.

The different layers of the skin (stratum corneum, epidermis, dermis, subcutis) have various antioxidant defenses to protect against exposure to environmental stressors such as ozone or UV radiation, which are known to cause oxidative changes to lipids,^{[375][376][377]} proteins,^[378] and DNA.^[379][380] 

Vitamin E as α-tocopherol is the predominant vitamer in human skin,^[377][381] present at concentrations approximately 10-fold higher relative to γ-tocopherol.^[381][382] The concentrations of α-tocopherol in these tissues under normal conditions have been noted to be 31+/-3.8nM per gram of tissue (epidermis^[381]), 16.2nM/g (dermis^[381]), 33+/-4nM/g (stratum corneum^[377]), and highest (76.5+/-1.5nM/g^[383]) in sebum whereas the concentrations of γ-tocopherol have been reported to be 3.3+/-1nM/g, 1.8+/-0.2nM/g, 4.8+/-0.8nM/g, and 8.7+/-1.8nM/g respectively.

Vitamin E is one of the first oxidative biomarkers to be depleted in response to environmental stressors in these cells.^[377] Moreover, depletion can occur below the point where skin would normally redden from such stressors (known as the minimal erythema dose or MED). Vitamin E can become depleted by over 50% in the stratum corneum,^[377] although this skin layer sees a more drastic reduction than others due to low concentrations of other co-antioxidants such as Vitamin C.^[384] Vitamin E depletion may be induced directly by absorption of UVB rays or indirectly, by free radicals produced by UVA rays.^[385] Ozone, an oxidant thought to only affect the outermost skin layers and not diffuse further,^[375] is also scavenged by vitamin E.^[386]

Both α-tocopherol and γ-tocopherol (forms of vitamin E) are present in the skin, buffering oxidative damage from the environment. Vitamin E is the predominant antioxidant in the outermost layer of the skin (stratum corneum), whereas the antioxidant potential of vitamin E is shared with that of vitamin C in lower layers of the skin.

Vitamin E may prevent signs of aging in skin, as the addition of vitamin E in vitro can restore the synthesis of collagen and prevent the accumulation of glycosaminoglycans (GAGs) due to damage caused to fibroblasts by reactive oxygen species (ROS).^[387] Such a preservation of collagen synthesis has also been noted with antioxidant enzymes such as catalase, suggesting a general oxidative role rather than one unique to vitamin E.^[388]

In both normal and diabetic rats, α-tocopherol at 200mg/kg oral intake was associated with less lipid peroxidation in serum and increased antioxidant enzymes in red blood cells.^[389] A later study using the same dose noted that vitamin E derived from palm oil (70% tocotrienols and 30% tocopherols^[390]) was of a greater potency than pure α-tocopherol;^[391] this being thought to be due to greater protective effects of tocotrienols in cells (neurons^[133]) and in sequestering free radicals in the cell membrane.^[392]

In humans, topical vitamin E (320 IU α-tocopherol per gram) applied to surgical scars over twelve weeks where one portion of the large scar was used as control failed to note any differences with vitamin E therapy relative to control therapy.^[393] It was noted that vitamin E application to scars was associated with the development of pruritis or redness, resulting in patients dropping out of the study.^[393] Reactions to topical vitamin E have also been noted elsewhere with burn scars, where up to 16.4% of subjects reported irritation while no benefits with vitamin E therapy were found.^[394] However, one study specifically assessing hypertrophic (raised) scarring and keloids (raised scars growing beyond the original boundaries of the wound), did find that the addition of vitamin E to reference therapy (silicon sheets^[395]) showed additional benefits.^[396]

In regards to skin aging, vitamin E may prevent oxidative damage to the skin based on test tube studies. While rat studies have shown systemic antioxidant benefits of vitamin E, the only human studies are with topical application and they mostly show no significant benefit to healing or scar appearance and in fact may promote possible irritation and reddening.

Hair loss (alopecia) is a condition associated with increased oxidative stress in the blood, even though the condition is not correlated with vitamin E levels.^[397] Since tocotrienols are more effective at reducing lipid peroxidation than α-tocopherol,^[392] they have been tested at 100mg orally over eight months in people with various forms of alopecia;^[398] mixed tocotrienol supplementation appeared to cause a 34% increase in hair count in balding areas relative to 0.1% seen in placebo, with only one nonresponder in the tocotrienol group and no significant influence on hair weight.^[398]

One study has noted a beneficial influence of tocotrienols on hair regrowth in balding people of both sexes. It is uncertain if these results would hold for other vitamers of vitamin E (such as α-tocopherol), and the study has not been replicated.

Primary dysmenorrhea is characterized by pelvic pain associated with menstruation in the absence of lesions, and its pathophysiology involves increased prostaglandin production.^[399] It is plausible that vitamin E could infuence dysmenorrhea since it is known to affect arachidonic acid production and its conversion to prostaglandin,^[400] which has motivated studying its effects in humans.

A placebo-controlled trial involving treating teenaged girls with primary dysmenorrhea with 500IU vitamin E daily for 2 days before through 3 days after the beginning of menstruation found that vitamin E reduced pain significantly compared to placebo at 2 months of treatment.^[401] A follow-up study in a similar population and same dosing schedule but a slightly lower dose (400IU daily) confirmed that vitamin E lowered not only pain intensity, but also pain duration and menstrual blood loss at both 2 and 4 months.^[402] A third study with a slightly extended age range (18-25) also confirmed that 400IU vitamin E daily using the same dosing schedule reduced pain.^[403] It should be noted that while all three studies showed greater improvement with vitamin E when compared with placebo, all the studies also showed significant improvement in the placebo groups as well, and the difference in pain between the vitamin E and placebo groups was only approximately 1 to 2 points on 10-point scale after 2 months of treatment;^{[401][402][403]} there was a more marked improvement in pain after 4 months of treatment with vitamin E when compared with placebo, however (approximately a 5 point difference).^[402]

400-500IU vitamin E daily taken 2 days before through 3 days after the onset of menstruation may reduce the symptoms of primary dysmenorrhea in young women.

Alzheimer's disease (AD) is in part characterized by oxidative damage in the brain.^[404] Vitamin E (α-tocopherol) could therefore hypothetically be a therapeutic agent for Alzheimer's disease (AD) since, in vitro, it can reduce lipid peroxidative damage in brain cells^[405] and cell death associated with β-amyloid protein toxicity.^[406] However, it has been noted that other vitamers beyond α-tocopherol may play a role in mild cognitive impairment and AD, since γ-tocopherol, β-tocotrienol, and total tocotrienol levels have been seen to be associated with a reduced risk of these states, while α-tocopherol was not.^[407]

The antioxidant properties of Vitamin E could theoretically be protective of neurons during Alzheimer's disease, as AD is a disease state characterized by high oxidative damage in the brain, and some vitamers of vitamin E have been associated with a decreased risk of developing either mild cognitive impairment or Alzheimer's disease.

A study involving supplementation of 2,000 IU Vitamin E (as α-tocopherol) either in isolation or with the glutaminergic antagonist memantine in people with mild to moderate AD already taking an acetylcholinesterase inhibitor noted that, over the course of five years of supplementation, the Vitamin E group experienced less cognitive decline as assessed by the ADCS-ADL rating scale representing a 19% slowing of disease progression per year relative to placebo.^[408] This change outperformed memantine in isolation, which had statistically nonsignificant benefits, and combination therapy provided no further benefits.^[408] This study reflects previous research where 2,000 IU of α-tocopherol in persons with moderate to severe AD benefitted when vitamin E was given either alongside selegiline (acetylcholinesterase inhibitor) or in isolation.^[368]

It has been noted^[409] that the above studies are in patients with mild to severe AD, whereas studies of vitamin E in older individuals without AD but with mild cognitive impairment have not had promising results.^[410] Moreover, vitamin E supplementation failed to demonstrate cognitive benefits in otherwise normal, healthy people.^[148][3] In persons with cognitive decline who then went on to develop Alzheimer's disease during the course of the study, Vitamin E (2,000 IU) exerted no protective effect or risk reduction relative to placebo.^[410]

Very high dose vitamin E supplements appear to be attenuate disease progression in mild to severe Alzheimer's disease, although the effects of lower doses in this cohort have not been tested and Vitamin E does not appear to benefit people with mild symptoms or cognitive decline not due to AD.

A meta-analysis of observational studies published between 1996 and 2005 revealed that supplementation with vitamin E may have a protective effect against Parkinson’s disease.^[411] Moreover, it has been noted that vitamin E increases in specific brain regions in patients with Parkinson’s disease, a possible compensatory mechanism following oxidative damage.^[412] This further suggests bolstering vitamin E levels with supplementation may help to limit oxidative damage associated with Parkinson’s. When investigated in vitro, vitamin E attenuates oxidative damage of striatal dopaminergic neurons, a phenomenon associated with the pathology of Parkinson's.^[413] Vitamin E deficiency does not appear to increase susceptibility of this brain region to oxidative stress in a mouse-model, however.^[414] 

In a rotenone-induced Parkinson's model in rats (rotenone being a toxin which causes Parkinson's-like symptoms^[415]), intramuscular administration of vitamin E (α-tocopherol, 100IU/kg bodyweight) attenuated pathological reductions in dopamine and increases in lipid peroxidation.^[416]

In contrast, the DATATOP study in humans which investigated the effects of selegiline, vitamin E (2,000 IU daily as α-tocopherol), or their combination failed to find any protective effects with vitamin E supplementation relative to placebo.^[417]

While very high-dose vitamin E seems to have some benefit in rodent models of Parkinson's disease, the lone human study on vitamin E and Parkinson's using a superloading protocol (same dose as studies in Alzheimer's disease) failed to find any protective effects. This suggests there may be no benefits to vitamin E supplementation for Parkinson's disease.

Vitamin E (as α-tocopherol) has been noted to reduce the toxicity of cerebrospinal fluid (CSF) from people with ALS against healthy neurons in culture, although the concentration used (250µM^[418]) was significantly higher than normally present in CSF (30-32.5nM^[109]). This is not a property unique to vitamin E, however, as protective effects have also been noted with other antioxidants in vitro.^[418]

Concentrations of vitamin E (as α-tocopherol) in the cerebrospinal fluid (CSF) of people with sporadic ALS has been noted in one study to be approximately 31% of those found in healthy controls, while α-tocopherol quinone was reduced by 75%.^[419] In contrast, a larger study of those with sporadic ALS failed to find such a reduction in α-tocopherol (α-tocopherol quinone was not measured) or any relationship between CSF α-tocopherol levels and disease duration or age of onset.^[109] Moreover, α-tocopherol levels in serum do not appear to be significantly influenced in people with sporadic ALS.^[420][421]

Tocopherol quinone is an oxidative byproduct of tocopherol, so an increased ratio of tocopherol quinone to tocopherol is an indicator of increased oxidative stress.^[422] Tocopherol dihydroquinone, a metabolite of tocopherol quinone, is a known antioxidant, however.^[423][424] Despite α-tocopherol serum concentrations under normal conditions being somewhat maintained in the 20-30µM range, concentrations of tocopherol quinone are normally quite variable (in the range of 15-980nM), even in healthy controls.^{[425][426][427]} Thus, the relevance of the lone study that associated low tocopherol quinone concentrations with ALS^[419] is uncertain.

Vitamin E concentrations (as α-tocopherol) have been measured in the blood and cerebrospinal fluid of those with ALS relative to healthy controls, but there does not appear to be any significant difference between groups.

In assessing serum α-tocopherol concentrations in a secondary data analysis from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, it was noted that males with serum vitamin E levels above the median value had a relative risk of 0.56 in developing ALS when compared to the males below the median value, although this trend was found by pooling the serum levels of all patients, whether or not they supplemented α-tocopherol.^[428] This study failed to find a protective effect of α-tocopherol supplementation for ALS, however, although this could be due to the insufficient statistical power of the study.^[428] One other study examining dietary and supplemental vitamin E intake and risk of developing ALS noted a protective effect in the highest quartile of dietary vitamin E intake relative to the lowest. Although this failed to reach overall statistical significance, long-term supplementation with vitamin E did show a statistically significant protective effect for ALS that increased with time.^[429]

Limited evidence suggests that high serum α-tocopherol levels may be correlated with lower risks of developing ALS. Studies examining α-tocopherol supplementation to date have had mixed results, however, suggesting at most that long-term (but not short term) α-tocopherol intake may protect against ALS. Further research is needed to confirm this finding.

Ataxia with vitamin E deficiency is a rare autosomal recessive neurodegenerative disease caused by mutations in the TTPA gene.^[430][431] The TTPA gene is expressed almost exclusively in the liver, and encodes the alpha-tocopherol transfer protein (alpha TTP) that specifically binds the alpha tocopherol form of vitamin E, facilitating its transfer between different cell membranes.^{[432][433][434]} When this rare mutation is present, the capacity to incorporate alpha-tocopherol into very low density lipoproteins secreted by the liver for distribution into plasma and tissues in the rest of the body is impaired.^[435] This causes a systemic vitamin E deficiency that particularly affects the nervous system, as neurons are particularly vulnerable to free-radical damage.^[436] AVED is characterized by neurological symptoms including ataxia (loss of muscle control), dysarthria (a motor speech disorder, associated with loss control of muscles in the face, mouth, and respiratory system), hyporeflexia (impaired or absent reflexes), and cardiomyopathy, among others.^[437] In patients afflicted with this rare genetic disease, vitamin E supplementation has been shown to be effective in improving symptoms and preventing disease progress.^[438][435] In one instance in particular, a case report of an 8-year old girl with AVED demonstrated that high-dose vitamin E supplementation (1200-1500mg/day, until serum vitamin E was elevated to normal, healthy levels) reversed nearly all of the disease symptoms^[438] and prevented progression of the disease.

Ataxia with vitamin E deficiency (AVED), is a rare genetic disease affecting vitamin E transport that is characterized by various neurological disorders. In patients afflicted with this disease, high dose vitamin E supplementation reverses many of the symptoms and prevents disease progression.

Polyunsaturated fatty acids (PUFAs) are fatty acids with more than one double bond. Since double bonds may be oxidized, the more double bonds there are in a fatty acid, the more susceptable it is to lipid peroxidation; PUFAs are the most susceptable, those with a lone double bond (MonoUnsaturated Fatty Acids or MUFAs) being less so, and saturated fatty acids being mostly immune to oxidation under standard conditions.^[439][440]

It has been noted that while an increase in lipid peroxidation (which occurs from oral ingestion of high doses of PUFA which are then integrated into organ tissue^[441][442]) from feeding rats PUFAs is not as high as expected, this difference is not completely accounted for by vitamin E levels in rats given adequate vitamin E intake in the short term,^[443] [444] although a vitamin E-deficient diet clearly does lead to increased peroxidation and damage. ^[445] It is thought by some, however, that increasing dietary PUFAs may increase the requirement of vitamin E.^[446][447] The increased need of vitamin E is known to correlate with the degree of fatty acid unsaturation, with more highly-saturated PUFAs reducing vitamin E stores more.^[448]

An adequate oral intake of vitamin E in humans has been estimated to be 0.6mg (approximately 1 IU) of α-tocopherol per gram of linoleic acid^[447] and may be higher for fatty acids with more than two double bonds (most dietary PUFAs).^[447]

Adequate vitamin E intake is necessary to prevent unsaturated fatty acids from becoming oxidized. Highly unsaturated fatty acids are more susceptable to oxidation than less unsaturated (or more saturated) ones. Preventing fatty acid oxidation reduces bodily vitamin E stores, so increasing dietary intake of unsaturated fatty acids should come alongside an increase in vitamin E intake (with the overall intake of vitamin E being thought to be at least 1 international unit per gram of unsaturated fatty acid).

Sesamin is a lignan from sesame seeds, and is an inhibitor of the process of Tocopherol-ω-hydroxylation (via CYP4F2 enzymes).^[449] This process metabolizes the vitamin E vitamers, and works more readily on the gamma vitamers (γ-tocopherol and γ-tocotrienol).^[449] Thus inhibiting it with sesamin has caused either inherent increases in plasma γ-tocopherol and γ-tocotrienol concentrations^[450][451] or augmentation of diet- or supplement-induced increases in plasma and tissue levels in rats.^[452][453] This has been confirmed in human men given sesame oil in food which contained 94mg sesamin (and 42mg of the related lignan sesaminol), which halved the excretion of γ-tocopherol metabolites in the urine over the course of 72 hours.^[454]

Sesamin inhibits the metabolism of vitamin E vitamers (via inhibiting tocopherol-ω-hydroxylation), and since this process works fastest on the gamma vitamers (γ-tocopherol and γ-tocotrienol) oral ingestion of sesamin will cause an increase in or augment the increase of plasma and tissue γ-tocopherol and γ-tocotrienol.

Procyanidin molecules from grape seed extract have been noted to protect membrane stability in erythrocytes (red blood cells) from radiation-induced oxidation.^[455] A concentration of 0.1-10µM of procyanidins have shown synergistic actions with the α-tocopherol content of red blood cells.^[456][457]

At least in vitro, vitamin E appears to be synergistic with procyanidins from grape seed extract in exerting antioxidant effects on cell membranes.

In the process of protecting unsaturated lipids from oxidation, vitamin E forms hydroperoxides as byproducts^[458] which are readily reduced by the selenoprotein^[459] phospholipid hydroperoxide glutathione peroxidase.^[460] In this manner, both vitamin E and selenium can act together to alleviate oxidative stress in certain tissues.^[461]

Some studies have combined vitamin E supplementation with CoQ10 on the assumption that vitamin E could improve absorption of the lipophilic CoQ10.^[462]

One study has noted that administration of supplemental vitamin E (1,200mg α-tocopherol) prior to an exercise test reversed the expected reduction in serum CoQ10 from exercise-induced oxidation (39%) into a mild increase (8.5%).^[463]

Vitamin E works synergistically with Alpha-Lipoic Acid, as ALA recycles vitamin E in the same manner as vitamin E can recycle vitamin C.^[464][465]

They also show synergy in anti-clotting of the blood, which could be cardioprotective or pro-hemorhhagic depending on dose.^[168]

Vitamin K is a vitamin most well known for its involvement in coagulating blood, and works via a series of proteins known as 'vitamin K dependent proteins' which are bioactivated in concert with bodily vitamin K stores.

Vitamin E by itself does not necessarily increase clotting time in otherwise healthy adults either over short (up to 800 IU^[274]) or long term (up to 800 IU^[178][251]) supplementation, but it has been noted to significantly augment coumarin-based anticoagulants such as warfarin (which are vitamin K antagonists).^[466][467] 

The role of vitamin K and its activity in these effects of vitamin E are uncertain, as while one study failed to note any adverse effects of vitamin E supplementation (900 IU α-tocopherol) on a biomarker of vitamin K status known as PIVKA-II^[93] another study using a more precise measuring device and 1,000 IU over 12 weeks found a modest increase (indicative of reduced vitamin K status^[468]) despite the other indicators of vitamin K status (carboxylated osteocalcin and plasma phylloquinone) being unaffected.^[469]

Vitamin E is known to augment the action of a class of vitamin K antagonists (the coumarin-based anticoagulants like warfarin). The current evidence is unclear, however, as to whether vitamin E plahys a direct or practically significant role in vitamin K status or activity.

Lycopene is a carotenoid that is inherently present in LDL particles alongside vitamin E (as both α-tocopherol and γ-tocopherol)^[151] and alongside other carotenoids^[470] as both groups (carotenoids and tocols) are fat soluble, requiring that they be transported around the body via lipoproteins.^[471][472]

It has been noted that lycopene and vitamin E have synergistically inhibit LDL oxidation in vitro.^[473]

When other factor are controlled for, high dosages of Vitamin E supplements (exceeding 400 IU daily) are associated with increase mortality from all causes,^[363] however these results have been contested by other analyses^[474][475] and counter points given in response to those.^[476][477] Some researchers have suggested that while indiscriminate vitamin E supplementation is not warranted based on the current evidence, the possibility that some subgroups may benefit from it remains an open one.^[478]

Tocotrienols could theoretically be a safer alternative than vitamin E in helping stop the spread of cancerous cells, since they possess higher bioactivity (thus needing a lower dose to exert the same effect) and accumulate in tissues and tumors rather than in the blood; these purported benefits are mostly hypothetical at this point in time, however, and more research is needed to confirm them.^[479]

Topical application of vitamin E (as α-tocopherol) has, at times, been noted to cause more reddening (erythema) and irritation when applied to scars than do control gels not containing vitamin E.^[393][394] Other reports suggest instances of contact urticaria, eczematous dermatitis, and erythema multiform-like reactions when vitamin E is applied to broken skin (such as after chemical peel or dermabrasion).^[480][481] It has been hypothesized that oxidized vitamin E derivates could act as haptens or irritants in these instances.^[481]

When vitamin E is applied topically to an area of the skin which is abrased or scarred, it appears to be associated with more frequent instances of erythema (reddening) and irritation than do control gels. For this reason, topical application of vitamin E for the purposes of healing scars is not generally recommended.