This article [Hartman et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11170129)] shows that supplementation with only 50 mg of d,l-alpha-tocopheryl acetate [equivalent to 34 mg of "d-alpha-tocopherol" or 34 "tocopherol equivalents" or 50 IU of "vitamin E" (http://www.ajcn.org/cgi/reprint/48/3/612.pdf)] (I don't understand the rationale for using the IU units, and the whole system of expressing things in IU should be abandoned immediately. I honestly still don't understand the conversions and don't intend to learn about them in any more depth.) The main point is that all-racemic (a 50-50 mixture of R and S chirality for each of the three chiral carbons on the side chain) alpha-tocopheryl acetate is roughly 50 percent as potent, in terms of changes in serum vitamin E over time (not bioavailability, given that I'm talking about steady-state serum tocopherol concentrations) and affinity for alpha-tocopherol transfer protein, as either d-alpha-tocopherol acetate or unesterified, d-alpha-tocopherol is. So 50 IU of "vitamin E" decreased serum testosterone and androstenedione levels in humans, and the authors cited all sorts of other research that had shown that vitamin E supplementation had produced either antiandrogenic effects or decreases in serum thyroid hormone levels [Tsai et al., 1978: (http://www.ncbi.nlm.nih.gov/pubmed/347918)(http://www.ajcn.org/cgi/reprint/31/5/831.pdf)], etc. Also, Hartman et al. (1999) [Hartman et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10624701)] found that serum tocopherol concentrations were inversely associated with serum testosterone and serum androstenedione concentrations in older men, and that suggests that higher doses of vitamin E [higher than the miniscule dose of 50 IU that actually decreased serum testosterone in a statistically significant way (Hartman et al., 2001)] could produce even greater decreases in serum androgens (mainly androstenedione, dihydrotestosterone, and testosterone). Vitamin E, especially in the form of vitamin E succinate, also can inhibit androgen receptor expression or inhibit the transcriptional response to androgen receptor activation by androgens, in epithelial cells of the prostate [Zhang et al., 2002: (http://128.151.10.65/george-whipple-lab/documents/yeh-papers/CVY63.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12032296); Huang et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19420015)] and probably in other cell types also, and there's a lot of excitement about the potential usefulness of vitamin E, as an antiandrogenic compound, in the treatment of or prevention of prostate cancer, etc. (http://scholar.google.com/scholar?q=%22vitamin+E%22+androgen&hl=en&btnG=Search&as_sdt=100000001). This antiandrogenic effect of vitamin E supplementation, in concert with its capacity to competitively inhibit the binding of ubiquinone to succinate dehydrogenase and other respiratory chain enzymes and thereby produce either a pro-oxidant and pro-apoptotic effect [Dong et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18372923)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668987/pdf/nihms100471.pdf)] or, via its conversion into tocopheryl quinone, an "antioxidant" effect (that's not much of an antioxidant mechanism, to inhibit complex I and II activity), would potentially be a problematic effect in many cases, in my opinion, such as in the absence of legitimate evidence of prostate cancer or benign prostatic hypertrophy/hyperplasia. It may well be that some derivative of vitamin E succinate will turn out to be less problematic, in terms of antiandrogenic side effects, than other approaches to the prevention of prostate cancer or the recurrence of prostate cancer, and so I can't completely dismiss the usefulnesses of some of these things. I generally think that the research on vitamin E supplementation shows beneficial effects in the short term, in a lot of contexts, but doesn't really look at the long-term effects. In my experience, vitamin E supplementation has seemed to be beneficial in the short term, in some contexts [such as in some sort of viral illness or the like (although I wouldn't suggest that any very specific benefits occurred)], but not really very much in the long term. For example, there's research showing that vitamin E can decrease microglial activation and produce other anti-inflammatory effects, but how much research looks at all the complexity of the long-term effects of vitamin E compounds? I've decreased to about 10-20 IU or something of supplemental vitamin E, and I obviously can't make any sort of recommendation to anyone. But when an article shows that severe vitamin E deficiency or mutations in alpha-tocopherol transfer protein can produce skeletal muscle myopathy and cerebellar ataxia, as many articles have shown [(http://scholar.google.com/scholar?hl=en&q=tocopherol+ataxia&btnG=Search&as_sdt=100000001&as_ylo=&as_vis=0); (http://scholar.google.com/scholar?hl=en&q=tocopherol+myopathy&btnG=Search&as_sdt=100000001&as_ylo=&as_vis=0)], that doesn't mean that one needs to take 400 or 800 IU or even 200 IU to prevent myopathy or ataxia from occurring. The RDA of 200 IU or whatever it is sounds totally arbitrary to me, and I'm honestly not convinced that vitamin E is necessarily essential. There's more evidence that it's essential than there is evidence that vitamin K1 and compounds within the vitamin K2 series are essential, but the fact that loss-of-function mutations in alpha-tocopherol transfer protein (a-TTP) produce ataxia doesn't mean that vitamin E's antioxidant effects prevent ataxia. It might mean that a-TTP exerts all sorts of functions that don't have anything to do with vitamin E transport. Just because an enzyme exists that is called "vitamin K 2,3-epoxide reductase" doesn't mean that vitamin K is essential or that there aren't many other functions and substrates of the enzyme or multienzyme complex. (Incidentally, I have an article in which the authors say that the vitamin K requirements of either mice or rats or both are 100 times those of humans. I can't find it at the moment, but that should raise red flags that something is wrong with the notion of the essentiality of vitamin K, in my view. Why would that be the case? It lends credence to the notion that it's not essential, in my view, and I'm not sure I know how to say why that's the case.)
The mechanisms by which vitamin E may decrease serum androgens are potentially worrisome to me, and androgen deprivation per se has the potential, in my opinion, in view of the research, to worsen the progression of cardiovascular disease and liver disease [Mu et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19453544)] and to increase the risk of type II diabetes [Saad et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/20126841)(http://www.abem-sbem.org.br/public/uploads/02_reviso_ABEM_538.pdf)]. I think the adverse effects of androgen deprivation would be just as detrimental to women as to men, but that's just my opinion. In addition to the fact that both women and men "need" testosterone, one might expect androgen deprivation to indirectly augment the potentially-adverse effects of estrogen replacement therapy on smooth-muscle-cell proliferation or autoimmune disease, for example, thereby lessening the therapeutic effects, etc. That said, some of the research on the sexually-dimorphic aspects of androgen metabolism in the liver sheds light on the ways in which the antiandrogenic effects of vitamin E could, in my opinion, potentially become problematic in some cases. And much of the research on the adverse effects of androgen deprivation has been done only in male humans or animals, for some reason. I should add that I think that the research that supposedly shows sexually-dimorphic aspects of androgen deprivation is not actually showing that, but the effects on men are more readily apparent, from a statistical standpoint, for example, because of the higher levels of serum and intracellular (hepatic) androgens in men. Traish et al. (2007) [Traish et al., 2007: (http://www.antonioaversa.net/public/PDF/9.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17727347)] made this observation in relation to research that had supposedly shown no correlation between plasma testosterone levels and the effects that testosterone clearly elicits in both men and women [see discussion of references 62 and 63 on p. 1226 of Traish et al. (2007)]. Traish et al. (2007) noted that the lower plasma levels of testosterone in women may decrease the robustness of or even serve to abolish statistical associations between plasma testosterone levels and testosterone-mediated effects in women, but the authors argued that investigations into the correlations between the plasma concentrations of dehydroepiandrosterone sulfate (DHEA-S), which is converted into androgens much more readily in women than in men, and androgen-mediated effects, in women, were more likely to be fruitful than attempts to show correlations between plasma androgens and androgen-mediated effects in women (Traish et al., 2007). I should mention that I don't think the use of exogenous DHEA is likely to be advisable, except under a doctor's supervision, and DHEA can produce strange effects on lipid and energy metabolism, etc. Traish et al. (2007) noted the tendencies toward "therapeutic nihilism" in relation to androgen metabolism in women, and, in general, a lot of the research on androgens in women seems strange to me. In this article, for example, [Andersson et al., 1994: (http://www.ncbi.nlm.nih.gov/pubmed/8062607)], the authors reported that the degrees of adiposity and insulin resistance correlated positively with plasma testosterone in women but negatively with plasma testosterone in men. But increases in adiposity are known to increase aromatase (CYP19, a cytochrome P450 enzyme that converts androgens into estrogens) expression in adipocytes and, presumably, also in all sorts of different cells in the brain and throughout the body. It seems likely that the elevations in androgens are not causing obesity or insulin resistance in women but are part and parcel of pre-obesity-or-obesity-associated endocrinological derangements, and obesity has generally been associated, as one would expect, with increases in estrogen-mediated effects or even disease processes, such as the development of breast cancer in women [Lorincz and Sukumar, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16728564)]. It seems that inter-individual differences in the transcriptional responsiveness to androgens and perhaps the local conversion of estrogens into androgens might be more important aspects or mechanisms of androgen metabolism, in women, at least, and probably also in men, than changes in plasma testosterone, or other androgens, alone would be.
Anyway, in relation to the antiandrogenic effects of vitamin E, vitamin E compounds are likely to produce decreases in serum androgens, in part, in my opinion, by serving as pregnane X receptor (PXR) agonists and thereby inducing CYP3A4 (the cytochrome P450 3A4 enzyme isoform) and CYP3A5 expression in the liver [Landes et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12504802)], and, in relation to the whole issue of gender and androgen metabolism, the protein content of CYP3A4 in the liver is twice as high in women as in men [Wolbold et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/14512885)]. But that doesn't mean that drug-or-nutrient-induced increases in CYP3A4 are less likely to be problematic in women than in men, in my opinion, to the extent that those increases may be problematic. CYP3A4 inducing drugs have been implicated in drug-induced antiandrogenic effects, and, for example, the induction of fatty liver disease in response to leuprorelin, a luteinizing-hormone releasing hormone receptor antagonist, was attributed to the antiandrogenic effects of leuprorelin [Gabbi et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18097299)]. Androgen deprivation has also been implicated as a cause of depression, and the authors of this article discuss evidence that the incidence of depression has been found to inversely associated with serum testosterone [Saini et al., 2008: (http://www.endo.gr/cgi/reprint/358/17/1868.pdf)]. Anyway, I'll put the information on the induction of skeletal muscle myopathy, in response to high doses of vitamin E (as a competitive inhibitor of ubiquinone binding to mitochondrial respiratory chain enzymes), in another posting. Vitamin E also can induce CYP2B1, I think, and that hydroxylates androgens at a different position on the steroid ring than CYP3A4 does.
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