Vitamin D3 increases AR, but decreases DHT stimulatory effect on PCa cell growth

Science
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#1

This study describes a two-fold increase of AR transcripts in prostate cancer cells induced by vitamin D3, but a strong inhibitory effect on growth:

On a molar basis VD3 was the most effective antiproliferative agonist (ED50 = 10(-9) M). It completely neutralized the stimulatory effects of androgens. Growth inhibition was not due to a decrease in the concentration of androgen receptor: whereas atRA, 9cRA, and PA did not alter androgen receptor levels, VD3 provoked a twofold increase.

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I wonder if this might have something to do with an adverse reaction some of us have had to high doses of D3:

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#2

The thing is, my vitamin D levels become deficient to the point where I feel even worse fatigue wise than my PfS symptoms if I don’t supplement. Should I consider dropping 5000 iu a day down to maybe 2000?

#3

Consider this:

The recommended safe upper limit for supplemental vitamin D3 is 4,000 IU/day

…But, it’s not as if you’re exceeding that many-fold, as some have.

You might want to get periodic blood tests if you are concerned.

#4

I do get periodic blood tests, and the most recent one my doctor actually said I’m right in the sweet spot for vit D. I’m not good about taking it everyday though. Maybe I can switch it 2000 a day and be fine

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#5

Interesting. Does someone know, why vitamin D seems to be decreased in PFS patients?

(My theory: The lack of local DHT in the skin leads to thinner, dryer skin that has less capacity to produce vitamin D3 (like in old people)). Do you think that may be the reason?

#6

It’s difficult to speculate about this.

Steroid-modifying enzymes are dysregulated in PFS, so I wonder if CYP27A1 (sterol 27-hydroxylase) might be one of them?

There is also an association among multiple-sclerosis, low 5-ar and 3a-HSD activity, and low vit-D.

And a study that showed a 1.8-fold decrease in CYP27A1 in AR knock-out mice:
https://www.fasebj.org/doi/full/10.1096/fj.08-105726

#7
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#8

https://www.sciencedirect.com/science/article/pii/S0022202X15601609

Study found that androgens appear to inhibit sunlight-induced vitamin-D production by inhibiting DHCR7, an enzyme for de-novo cholesterol production.

To add to this, DHCR7 was found to be decreased by 2.7-fold in the skin of patients treated with Accutane after 8 weeks. Low vit-D is also common in PAS patients.

Just throwing some things out there.

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#9

Interesting. So we could also expect the vitamin D precursor, 7-dehydrocholesterol to be lowered in PFS. But why is it like that? I would have expected the opposite for this experiment. From a perspective of nature it doesn’t really make sense to inhibit Vitamin D production and not to undo a vitamin D deficiency?

And if androgenes mediate the inhibition of vitamin D in the skin, shouldn’t vitamin D levels be high in PFS then?

#10

Yeah. I don’t get it either. It was surprising.

If AR mediates the effects of androgen on vitamin D, AR overexpression could amplify the effect observed in the above study. That’s only a speculation though. There is literature showing a decrease of both AR and vitamin D in the back-skin of Accutane-treated patients.

I think this might be yet another one of those things where we don’t have enough information to fill in the blanks to make sense of it.

Vitamin D supplementation is also one of those things that seems to have an effect on post-drug patients, with anecdotal reports of drastic improvements and crashes on vit D.

#11

Well, with the mouse model I was a bit sceptical. Mice are mostly living in the dark and they have a thick fur. So I am a bit sceptical whether the vitamin D metabolism of mice is really comparable to humans.

We found a trend towards increased risk of hypogonadism in men within the lowest 25(OH)D quintile (≤43.9 nmol/L). In conclusion, our data suggest that men with very high 25(OH)D levels (>102 nmol/L) might be at an increased risk of hypogonadism. Furthermore, we observed a trend towards increased risk of hypogonadism in men with very low vitamin D levels indicating a U-shaped association of vitamin D levels and hypogonadism. With respect to risk of male hypogonadism, our results suggest optimal serum 25(OH)D concentrations of 82-102 nmol/L.

This, in my opinion my explain why some guys do well on vitamin D, but when they overdo it they may in up in a crash. Me myself I felt some overall improvements, but I also had terribly low vitamin D although I try to get as much sun as possible.

" Thus, it can be concluded that vitamin D3 delays testicular senescence by regulating proliferation and apoptosis."
https://www.nature.com/articles/s41598-019-50679-y

“The testes of vit. D-deficient rats showed incomplete spermatogenesis and degenerative changes. Although interpretation is complicated by the intricate communication among testis cell types, these data suggest that the Sertoli cell is a primary site of action of 1,25(OH)2D in the testis. Moreover, these data indicate that 1,25(OH)2D receptor function in the testis relates to germ cell division/maturation, although this may be an indirect effect via the Sertoli cells.”
https://www.sciencedirect.com/science/article/abs/pii/0022473189901052

“Vitamin D may have a stimulatory role on androgen production in men”
https://www.sciencedirect.com/science/article/abs/pii/S0960076019305680

" Epidemiological data have shown that vitamin-D deficiency is also associated with erectile dysfunction. In this review, our aim is to interpret the mechanisms by which vitamin-D might regulate anatomy and physiology of penis. Evidence showed that vitamin-D is needed for an adequate erectile function"

  1. Vitamin-D and androgen receptors

An extra mechanism of VD on erectile function seems to function via binding to T receptors. Computer ( in silico ) modeling shows that besides activating the VDR, 1,25-D displays high affinity for some of the body’s other nuclear receptors. This suggests that when 1,25-D increases above its normal range, it binds the α/β thyroid, the glucocorticoid, and the T receptors, displacing their native ligands [53]. Marshall [54] showed the symmetry with which endogenous ligands exhibited very similar affinities across some members of the type 1 nuclear receptor family [54]. For example, 1,25-D docked into the VDR with a (nanomolar) Kd of 8.48, but also exhibited a Kd of 8.05 into the T receptor.

VD is positively associated with T, exhibits a concordant seasonal changeability [47], elevates when T was supplemented in hypogonadism [48]. Surprisingly, the reverse situation is also true, suggesting that VD supplementation might increase T levels [49]. In a clinical randomized controlled trial, which is the first on this topic in literature, Pilz et al [49] investigated the effect of VD supplementation on androgens in men. The results were significant and the researchers observed that overweight men with VDD had a clinically meaningful increase in serum T levels after VD supplementation for 1 year [49]. Recently, it was also demonstrated that VD supplementation improves T levels, metabolic syndrome and erectile function in middle-aged VD deficient men [8]. Canguven

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#12

As I’ve said in other threads I don’t think low vit D is a direct consequence of pfs. I was found to have close to zero levels a year or so before I ever took propecia. Fixing my levels stopped these fevers I would get ever 2-3 months which was probably autoimmune related.

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#13

Did you fix these levels and stop the fevers before, or after, PFS?

#14

I found I had low levels and was given prescription dose in 2011. Almost right away I stopped having these flare up episodes and then I took propecia in September/October of 2012 and got pfs

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