How low vitamin D causes a high PSA

I tell everyone to sign up with ancan.org for their advanced prostate cancer meetings. You don’t even need to go to a meeting, but you get a weekly newsletter that has a tremendous amount of information.. I’ve already posted about the Prostox meeting that was in this week’s newsletter and here is some information about vitamin D and its effect on PSA.

When alert COO Bill Franklin was told by a Veteran he was advising that the man's PSA had jumped into the 8’s and by the way his Vitamin D level was profoundly low, Bill wondered if they were related. He called me (Dr. John Antonucci) and I looked into it.
It’s true: low levels of vitamin D are associated with elevated PSA levels. Now why would a gland buried deep where there is no sun, and only interested in reproduction, be in a relationship with Vitamin D?

That relationship is complex. Research shows:
Vitamin D insufficiency is associated with a higher risk of adverse effects from paclitaxel, a chemotherapy related to docitaxel. Might vitamin D supplementation help with adverse effects? (Ciao-Sin Chen)
In African American men, vitamin D deficiency is associated with increased odds of prostate cancer diagnosis on biopsy. In both European American and AA men, severe vitamin D deficiency was positively associated with higher Gleason grade and tumor stage. (Murphy)
In another study men were given 3000IU vitamin D or placebo and their testosterone levels were followed. Compared to baseline values, a significant increase in total testosterone levels were observed in the vitamin D supplemented group, and no significant change in testosterone in the placebo group, suggesting vitamin D supplementation might increase testosterone levels.
The incidence of prostate cancer and mortality is higher with low vitamin D throughout adulthood (Mucci). But do we have evidence that correcting low vitamin D is actually associated with a reduction in the risk of prostate cancer? No. (Ryan and Mucci)

In a Randomized Control Trial (RCT) of Vitamin D3 supplementation (4,000 IU/d) vs. placebo in men with prostate cancer under active surveillance there was no significant difference in PSA change after 1 year. High-dose vitamin D supplementation did not lower PSA levels or slow progression. (Marshall)
Similarly, the ProsD trial aimed to determine if oral vitamin D supplementation could prevent prostate cancer (PrCa) progression in men on active surveillance (AS), and found that it did not.(Visalini Nair-Shalliker)
In VITAL trial data, which randomized over 25,000 participants to Vitamin D3 (2,000 IU/d) or placebo, Vitamin D supplementation did not significantly improve overall survival or reduce PSA progression compared to placebo.(Chandler)
Recall that a high PSA in the setting of low vitamin D is not specific for cancer. It only signals that the prostate is more active or "leaky" for some reason, but does not prove cancer is present. While low vitamin D and high PSA are associated, the elevated PSA is not proven to be from prostate cancer—it could be from a variety of benign or inflammatory prostate conditions.

Is all this important? After all, what is the prevalence of Vitamin D deficiency? It depends on the definition. Studies in North America and Europe generally define Vitamin D deficiency as a serum 25-hydroxyvitamin D level below 20 ng/mL. Estimates of deficiency in men with prostate cancer typically range from 30% to 80%. (Murphy et al)
In Murphy's study, among 120 men with newly diagnosed, untreated prostate cancer in Chicago, 40% were vitamin D deficient and 32% were insufficient. (Cutoffs at 20 and 30 mg/ml)
Trump et al. (Ed: do we trust Trump numbers?) reported in a review that ~40–50% of men with prostate cancer are vitamin D deficient, and rates of insufficiency are even higher.
Bermingham reported in a meta-analysis of 21 studies, 54% of men with prostate cancer were vitamin D deficient.
These are amazingly high numbers.

What might be going on here? Here are some ideas:
- Vitamin D plays a key role in regulating cell proliferation (decrease), differentiation (increase), and apoptosis (increase) in prostate--and presumably prostate cancer--tissue.
- Adequate vitamin D levels may suppress abnormal cell growth and reduce inflammation, potentially limiting prostate tissue hyperactivity or benign hypertrophy, which can elevate PSA levels.
- Vitamin D has immunomodulatory and anti-inflammatory properties.
- Chronic inflammation in the prostate is associated with increased PSA levels, maybe by leading to PSA leakage into the bloodstream.
- Vitamin D interacts with androgen signaling pathways, which are central to prostate cancer biology. D-deficiency may alter androgen receptor activity, potentially leading to increased prostate cell activity or turnover, reflected as higher PSA.
- Vitamin D influences the prostate’s microenvironment by modulating growth factors, cytokines, and extracellular matrix components.
- Deficiency may therefore promote a pro-inflammatory, pro-proliferative environment, increasing PSA levels.
- Low vitamin D often correlates with reduced sun exposure, poor nutrition, or other health issues which may independently influence PSA levels or prostate health, confounding the association.
-Vitamin D levels are also inversely correlated with prostate volume.
-At high levels Vitamin D may even be bad for the prostate.

Whatever the mechanism is, let’s make sure our elevated PSA levels are not related to Vitamin D. There are of course many things that influence PSA levels. Try to get a Vitamin D level during the diagnostic process. Don't let the lab make you sign a self-pay paper, write me if insurance or Medicare won't pay. Vitamin D is found in fatty fish, egg yolks, and D-fortified cereals, OJ, real and plant milks, and sun.
By the way, despite some of the findings above, when Bill’s guy was put on vitamin D replacement, his PSA went down to the 3’s.

John (dr.john@ancan.org)

Editors Note: You will have picked this up from reading carefully, but be sure to test Vitamin D - Hydroxy 25