haidut

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Vitamin D is one of the most versatile substances in Peat world. It is actually a steroid and not a true vitamin, and as a steroid it is expected to have effects on other steroids. Its role in opposing estrogen, together with the other fat-soluble vitamins, is well-known. Now, this study shows that vitamin D prevent the deactivation of androgens by various glucuronidation enzymes, and this effect is especially pronounced for the strong androgens like DHT and androsterone. Even more interestingly, vitamin D requires the presence of the androgen receptor to exert its effects, suggesting that vitamin D binds to the androgen receptor, possibly as an agonist, since DHT also inhibits its own deactivation / glucuronidation through the same receptor. In conclusion, vitamin D inhibits the deactivation / glucuronidation of strong androgens, which leads to build up of androgens like DHT and androsterone, and that may explain some of the insulin-sensitizing and anti-obesity effects of vitamin D.

Calcitrol (1alpha,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells. - PubMed - NCBI

"...Calcitriol (1alpha,25-dihydroxyvitamin D(3)), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3alpha-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15- and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells"

"...To determine whether calcitriol affects androgen glucuronidation in prostate cancer cells, LNCaP cells were treated with vehicle or calcitriol (10 nmol/L) for 48 or 96 h, and glucuronidation assays were then done with cell homogenates in the presence of 3α-diol, ADT, or DHT (Fig. 1 ). The formation of all glucuronide conjugates was significantly reduced after 48 h of treatment with calcitriol, and the effect was even more pronounced after 96 h (Fig. 1). The strongest effect was observed for ADT-3G (56% reduction after 96 h) followed by DHT-17G (50% reduction after 96 h). These results show that calcitriol inhibits the glucuronide conjugation of DHT and its 5α-reduced metabolites 3α-diol and ADT in LNCaP cells."

"...Taken together, these different experimental approaches clearly show that calcitriol essentially requires a functional AR to inhibit the expression of the UGT2B17 gene, whereas it exerts its suppressive effects on the UGT2B15 gene in an AR-independent manner."

"...The observation that calcitriol drastically reduces androgen glucuronidation in UGT-expressing prostate cancer cells suggests that treatment with this molecule may have profound consequences for androgen homeostasis and activity in androgen-sensitive prostate cancer cells. Indeed, reduction of glucuronidation in LNCaP cells causes an accumulation of free androgens and higher cell proliferation rates (28, 39). Thus it is reasonable to speculate that, by reducing UGT expression, calcitriol will also result in DHT accumulation. In addition, DHT is a potent inhibitor of UGT2B15 and UGT2B17 expression and of its own glucuronidation (26, 28, 29). Therefore, the reduction of DHT glucuronidation caused by calcitriol may be further amplified through this negative autoregulatory loop. However, calcitriol also exerts numerous androgen-independent antiproliferative effects in prostate cancer cells and has been shown to be efficient for dampening prostate cancer cell proliferation (4, 7, 40, 41).
 
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Braveheart

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Vitamin D is one of the most versatile substances in Peat world. It is actually a steroid and not a true vitamin, and as a steroid it is expected to have effects on other steroids. Its role in opposing estrogen, together with the other fat-soluble vitamins, is well-known. Now, this study shows that vitamin D prevent the deactivation of androgens by various glucuronidation enzymes, and this effect is especially pronounced for the strong androgens like DHT and androsterone. Even more interestingly, vitamin D requires the presence of the androgen receptor to exert its effects, suggesting that vitamin D binds to the androgen receptor, possibly as an agonist, since DHT also inhibits its own deactivation / glucuronidation through the same receptor. In conclusion, vitamin D inhibits the deactivation / glucuronidation of strong androgens, which leads to build up of androgens like DHT and androsterone, and that may explain some of the insulin-sensitizing and anti-obesity effects of vitamin D.

Calcitrol (1alpha,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells. - PubMed - NCBI

"...Calcitriol (1alpha,25-dihydroxyvitamin D(3)), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3alpha-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15- and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells"

"...To determine whether calcitriol affects androgen glucuronidation in prostate cancer cells, LNCaP cells were treated with vehicle or calcitriol (10 nmol/L) for 48 or 96 h, and glucuronidation assays were then done with cell homogenates in the presence of 3α-diol, ADT, or DHT (Fig. 1 ). The formation of all glucuronide conjugates was significantly reduced after 48 h of treatment with calcitriol, and the effect was even more pronounced after 96 h (Fig. 1). The strongest effect was observed for ADT-3G (56% reduction after 96 h) followed by DHT-17G (50% reduction after 96 h). These results show that calcitriol inhibits the glucuronide conjugation of DHT and its 5α-reduced metabolites 3α-diol and ADT in LNCaP cells."

"...Taken together, these different experimental approaches clearly show that calcitriol essentially requires a functional AR to inhibit the expression of the UGT2B17 gene, whereas it exerts its suppressive effects on the UGT2B15 gene in an AR-independent manner."

"...The observation that calcitriol drastically reduces androgen glucuronidation in UGT-expressing prostate cancer cells suggests that treatment with this molecule may have profound consequences for androgen homeostasis and activity in androgen-sensitive prostate cancer cells. Indeed, reduction of glucuronidation in LNCaP cells causes an accumulation of free androgens and higher cell proliferation rates (28, 39). Thus it is reasonable to speculate that, by reducing UGT expression, calcitriol will also result in DHT accumulation. In addition, DHT is a potent inhibitor of UGT2B15 and UGT2B17 expression and of its own glucuronidation (26, 28, 29). Therefore, the reduction of DHT glucuronidation caused by calcitriol may be further amplified through this negative autoregulatory loop. However, calcitriol also exerts numerous androgen-independent antiproliferative effects in prostate cancer cells and has been shown to be efficient for dampening prostate cancer cell proliferation (4, 7, 40, 41).

Interesting...another plus for D...have been confused for a long time trying to understand the safety and effectiveness of D...but recently have come to an understanding on how to incorporate it in my life...always keeping watchful eye over my prostate, this post is good news no? Currently getting subtropical sun for 30 minutes at least 3 days a week...liver once a week...keeping magnesium and calcium up...Estroban on days I don't get sun...not sure how best to incorporate it into my protocol...
 

milk_lover

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So taking D3 with pregnenolone is a reasonable approach? I don't know if it's a strong androgen.
 
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haidut

haidut

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So taking D3 with pregnenolone is a reasonable approach? I don't know if it's a strong androgen.

I think taking D with DHEA or Pansterone would be even better. Lower dose pregnenolone will convert somewhat into DHEA but most of it will go down the progesterone pathway, so not much androgens will get produced if only pregnenolone is taken.
 

milk_lover

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I think taking D with DHEA or Pansterone would be even better. Lower dose pregnenolone will convert somewhat into DHEA but most of it will go down the progesterone pathway, so not much androgens will get produced if only pregnenolone is taken.
Thanks haidut! so do you have a rough estimate of the D3 dose needed to amplify the effect of let's say 5 mg of DHEA?
 
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haidut

haidut

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Thanks haidut! so do you have a rough estimate of the D3 dose needed to amplify the effect of let's say 5 mg of DHEA?

Any dose would help, it was a dose dependent response.
 

jandrade1997

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This actually strikes me as negative news, not positive news. This is showing that vitamin D suppresses enzymes involved in glucuronidation, including those involved in the excretion of estrogens. Peat has warned us about substances that interfere with glucuronidaiton, in particular polyphenols.
 
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haidut

haidut

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This actually strikes me as negative news, not positive news. This is showing that vitamin D suppresses enzymes involved in glucuronidation, including those involved in the excretion of estrogens. Peat has warned us about substances that interfere with glucuronidaiton, in particular polyphenols.

Yes, in theory it could also affect estrogen levels but the study did not say anything about that. Also, higher vitamin D levels have been linked to lower serum estrogen levels, so if vitamin D was interfering with estrogen glucuronidation we should have seen the opposite results.
High blood levels of vitamin D linked to reduced estrogen – and potentially lower breast cancer risk
 

BigChad

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This actually strikes me as negative news, not positive news. This is showing that vitamin D suppresses enzymes involved in glucuronidation, including those involved in the excretion of estrogens. Peat has warned us about substances that interfere with glucuronidaiton, in particular polyphenols.

Which polyphenols? Does that include olive polyphenols and leaf extract
 

baccheion

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Does this effect in prostate cancer cells translate to the body in general? Did the dose-dependent effect peak at some point (say, after sufficiency was achieved)?
 

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