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Wednesday, July 4, 2007

Vitamin D and Prostate Cancer

[updated February 12, 2008]

Readers may wish to first view the fascinating Vieth presentation which is one hour but worth it. (Unfortunately the Vieth presentation seems to be no longer online.) Also readers may wish to review the NIH Vitamin D Fact Sheet, four papers by Donald L. Trump ([bio]), Lisa Tseng, Gerry Schwalfenberg and Michael Holicks, the presentation by Kevin Cahill and the Wikipedia entry.

Garland et al [PMID: 16380576] reviewed 30 colon cancer, 13 breast cancer, 26 prostate cancer, and 7 ovarian cancer studies as well as several that assessed the association of the vitamin D receptor genotype with cancer risk and concluded that the "evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects." (This refers to all types of cancers, not just prostate.)

The Canadian Cancer Society is the first major country-wide organization to come out in favor of mass vitamin D supplementation (1000 IU/day in spring and winter for Canadians and all year around for those at increased risk) suggesting that other organizations many follow.

Vitamin D can be obtained from sunlight, fatty fish, shitake mushrooms and supplements and other sources. While it appears that the skin has self-regulatory mechanisms to prevent toxicity from vitamin D from sunlight if the vitamin D is derived from supplements it may take different pathways that could have an adverse affect on athersosclerosis. See Tseng [link] who suggests caution on supplements. Also note that getting Vitamin D from the sunlight involves sun exposure which does increases one's risk of skin cancer although according to a [presentation] by Reihold Vieth the increased risk of skin cancer is much less than the reduced risk of all cancers.

Evidence


The following is suggestive of a protective effect for Vitamin D against prostate cancer:
  • People in northern climates, i.e. climates with less sunshine/vitamin D, have higher rates of prostate cancer.
  • Blacks (whose dark skin requires more sunshine to get the same level of vitamin D as whites) have higher rates of prostate cancer.
  • Cancer patients diagnosed in summer have better prognoses than those in other seasons (due to the protective effect of sunlight exposure).
  • Calcium in dairy reduces vitamin D levels and higher levels of calcium consumption have been associated with higher rates of prostate cancer.
  • Woo et al [PMID: 15749627] gave 15 prostate cancer patients 2000 IU of Vitamin D daily and found that PSA doubling time increased in 14 of the 15 with the median rising from 14.3 months to 25 months and initial decreases in PSA in 9 of the subjects. No adverse side effects were observed.
  • Haojie et al [link] conclude that prostate cancer patients have low levels of Vitamin D.

See [PMID: 15868450] and [PMID: 12668278].

Vitamin D Pathway


The following sequence of chemical reactions occur (see [Vitamin D], [Calcium] and [Vitamin D Pharmacology] and [link]):

  1. sunshine is converted to D3 in the skin (or D3 is ingested directly as vitamins or in food). D3 is also called cholecalciferol and can be obtained as a supplement without a prescription.
  2. D3 is converted in the liver to the circulating form of vitamin D known as calcidiol or 25(OH)D3. This will circulate in proportion to the amount consumed or sunlight exposure with a half-life of 10 to 19 days. The circulating form is thought to have a beneficial effect itself [PMID: 15860261] in addition to contributing to its conversion in the following point.
  3. The circulating form of vitamin D is converted in the kidneys to the active form also known as calcitriol or 1,25(OH)2D3. The active form has a relatively short half-life and is regulated by the parathyroid hormone so that a relatively stable level exists. The active form of vitamin D can be obtained as a prescription drug. Its current use in medicine is for patients with kidney failure or osteoporosis.
  4. Vitamin D receptors (VDRs) on cancer cells interact with the active form of vitamin D suppressing the growth of cancer cells.


We can summarize the above with this diagram

sunshine -> D3 -> circulating D -> active D -> Vit D receptors

or in terms of names:

sunshine -> cholecalciferol -> calcidiol -> calcitriol -> Vit. D receptors

or in terms of symbols:

sunshine -> D3 -> 25(OH)D3 -> 1,25(OH)2D3 -> VDRs


The conversion of D3 to circulating D is called hydroxylation as is the conversion of circulating D to active D.

In [PMID: 1586845] it is hypothesized that prostate cancers lose the ability to convert circulating D to active D and therefore may rely on active D that is itself circulating. Note that consumption of calcium (e.g. dairy products) suppresses the active form of vitamin D and this could explain the observed unfavorable effect of calcium consumption on prostate cancer.

Intervention in the pathway could be at several points:

  1. increase the load of D3 through supplements so that more of the active form of the vitamin D gets produced even if its not being converted efficiently (the first link points to such a study), or
  2. rather than increase vitamin D attempt to increase the sensitivity of the Vitamin D receptors (VDRs) on the cancer cells to the vitamin D that is already there through phytoestrogens such as Resveratrol (thought to be the active ingredient in red wine). This study is about the latter approach in breast cancer but presumably this idea could also apply to other cancers: [link]

Tests

The most commonly found assay is the radioimmunoassay that detects the 25(OH)D2 and 25(OH)D3 forms of the circulating form of vitamin D. Its coefficient of variability is 12% to 18% for vitamin D levels in the 85 - 145 nmol/L range and 10% - 25% for vitamin D levels in the 20 - 62.5 nmol/L range. Another test is the competitive binding protein assay which detects 25(OH)D2 and often gives readings 30% higher than the radioimmunoassay. See [link].

Tests are available to measure blood levels of calcidiol, 25(OH)D3, and calcitriol, 1,25(OH)2D3. (These are two separate tests.) The ratio of the levels of these two tests would presumably reveal the efficiency of conversion of 25(OH)D3 to 1,25(OH)2D3.

Dr. Donald L. Trump says: "available data suggest that all men with prostate cancer should measure their 25(OH) D3 level and take enough supplementation to assure blood levels in the normal range. Since it takes 8-12 weeks for a steady state level of 25(OH) D3 to be achieved, D3 supplementation should be adjusted no more often than every 3 months, guided by blood levels of 25(OH) D3." [link]

Dosage


The Canadian Cancer Society recommends that Canadians take 1000 IU per day of Vitamin D in fall and winter and those at risk of not getting sunlight in the other seasons take it all year round. The American and Canadian Cancer Societies and a number of other prominent organizations agreed at a 2006 Vitamin D conference in Toronto that 2000 IU/day was safe [link]. In [Full Text] [PMID: 10232622] , Reinhold Vieth suggests that 4,000 IU/day may be a safe dose and, in fact shows a dose-response curve in which he has marked the levels at which various studies observed toxicity. One study observed toxicity at 10,000 IU per day but all other studies did not observe toxicity until even higher levels suggesting that even an intake of 10,000 IU might be safe. In a response Muskiet et al (2001) [PMID: 11722970] question whether there is evidence that more than 4,000 IU is needed to prevent disease. They suggest that since the excess is stored in fat tissue, 4,000 IU might be safe in the short run but could be a "potential time bomb with an as yet poorly understood detonator" in the long run.

In his PCAAT article Dr. Donald Trump suggests that if "blood 25(OH) D3 levels are raised into the 32-100 nmol/L level, PTH levels decrease and loss of bone density improves in most individuals. Whether this level (32-100 nmol/L) reflects the optimal or ideal for any individual is not clear." The 32-100 nmol/L levels that Trump mentions correspond to 8 to 40 ng/mL. In this 2006 survey [PMID: 16825677] [Full Text] Bischoff-Ferrari et al conclude that optimum serum (i.e. blood) levels of "25(OH)D begin at 75 nmol/L (30 ng/mL), and the best are between 90 and 100 nmol/L (36–40 ng/mL)".

In a report written by the University of Ottawa for the Agency for Healthcare Research and Quality. Effectiveness and Safety of Vitamin D in Relation to Bone Health found "a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose". Dose-response cannot be assumed linear if it were then this would imply that a 1000 IU/day would raise serum levels by 10-20 nmol/L or 4-8 ng/mL. See the dose response curve in the Vieth paper (the same paper cited above) for better insight into the relationship.

Be sure to review the deficiencies and toxicities section of this page and note that higher dosages only be taken with sufficient medical monitoring. Also people with kidney, liver or heart disease may not be able to handle Vitamin D supplementation at all.

Functions of Vitamin D


Vitamin D increases the blood concentration of calcium affecting the balance of calcium and phosphorus in the body. It also may have much other broader functions as well that are not yet well understood.

Other effects of vitamin D are:

  1. Activates caspase-3
  2. Activates caspase-9
  3. Decreases ER-alpha
  4. Decreases bcl-2
  5. Kills mitochondria by means of a caspase-independent mechanism, resulting in cell death
  6. Increases AS3, a protein which shuts off prostate cancer (and breast cancer) proliferation
  7. reduces inflammation and prostaglandin secretion (which promote cancer cell growth)
  8. down regulates the COX-2 (which promotes cancer cell growth) acting in a similar way to NSAIDs such as aspirin (and Vioxx which was taken off the market due to concerns about serious cardiovascular side effects and GI bleeding).
  9. Vitamin D deficiency results in increased levels of parathyroid hormone and reduced bone density.
See [link] for first 6 and Kevin Cahill presentation for points 7 and 8.

Sources of Vitamin D


One can get vitamin D from sunlight, cod liver oil and supplements. The NIH Office of Dietary Supplements Fact Sheet gives additional sources.

Deficiency and Toxicity


"Vitamin D deficiency can lead to osteoporosis in adults or rickets (a bone disease) in children.

Too much vitamin D can make the intestines absorb too much calcium. This may cause high levels of calcium in the blood. High blood calcium can lead to calcium deposits in soft tissues such as the heart and lungs. This can reduce their ability to function.

Kidney stones, vomiting, and muscle weakness may also occur if you have too much vitamin D."

The above quote is from the Medline page on Vitamin D.

Vitamin D deficiency can result from insufficient sunlight exposure or insufficient consumption of vitamin D in the diet, liver disease or kidney disease or genetic defects in the body's vitamin D receptors. See [Mayo clinic].

According to an article by Dr. Trump mice genetically modified to have no vitamin D receptors exhibit low blood calcium, weak bones, hairless skin, abnormal muscle development, high blood pressure, abnormal heart muscle development, increased susceptibility to infection and increased susceptibility to blod clot formation.

Toxicity does not normally occur from sunlight exposure due to self-regulatory mechanisms in the skin; however, increased sun exposure does put one at increased risk for skin cancer; although, according to this Reihold Vieth presentation sun exposure increases risk of skin cancer by 1% - 2% but reduces risk of all cancers by 10% - 20% so it reduces overall cancer risk but much more than it increases skin cancer risk.

The self-regulatory mechanisms do not appear to exist when the vitamin D is consumed as through supplements. Since Vitamin D is fat soluble rather than water soluble, in principle, it can build up in fat stores to toxic levels. In an article by Lisa Tseng: "Concurrent with this rise in vitamin D ingestion in Canada, United States, Sweden, Israel, and England were the epidemic onsets of atherosclerosis and osteoporosis, which led Moon et al. to hypothesize that chronic vitamin D excess contributes to the development of these two illnesses. Moon and colleagues supported their postulate by citing 37 studies, some dated as early as 1945, which documented cardiovascular and skeletal effects similar to atherosclerosis and osteoporosis in humans and laboratory animals after high vitamin D intake. Subsequently, Haddad et al. showed in seven healthy human volunteers that while endogenously synthesized dermal vitamin D is transported on vitamin D binding protein and causes a more sustained increase in serum 25-hydroxy vitamin D, the orally administered vitamin D is absorbed from the intestinal tract via chylomicrons and carried in the circulation by lipoproteins such as VLDL and LDL, which may end up in the artery wall. This finding supports Fraser’s earlier speculation that the toxicity of orally acquired vitamin D might be due to its unnatural route through the body and, consequently, it is less finely regulated than endogenously synthesized dermal vitamin D."
[link]. Perhaps man evolved to regulate vitamin D from the sun since early man was constantly exposed to the sun but because consumption of large amounts of vitamin D through supplements is only possible with modern technology no similar mechanism evolved to regulate that.

In [PMID: 16598750] 2 of 37 patients taking vitamin D developed kidney stones.

In a February 2008 paper in Bioessays, Trevor Marshall writes that unlike getting vitamin D from the sun, vitamin D supplements may undesirably suppress immune function and supplements may actually block rather than enhance Vitamin D Receptor (VDR) activation: "the Vitamin D Nuclear Receptor (VDR) acts in the repression or transcription of hundreds of genes, including genes associated with diseases ranging from cancers to multiple sclerosis" and since we do not know the exact details of these numerous interactions they could include harmful ones. See [news] and [PMID: 18200565].

Because of the potential problems cited above it is important to monitor Vitamin D levels and urine calcium levels if consuming high dosages of Vitamin D.

Development of Vitamin D Analogues


The companies Cytochroma and Novocea Pharmaceuticals are working on analogues of calcitriol that avoid the side effect of hypercalcemia (excess calcium).

References



Gerry Schwalfenberg, Not Enough Vitamin D, Can Fam Physician 2007;53:841-854
[link]

Donald L. Trump, Vitamin D: More than a Hormone -- More than a Calcium and Bone Thing, Prostate Cancer Communication, Dec 2006, 22(4). [link]. Vitamin D and prostate cancer.

Marshall Protocol is a protocol based on Vitamin D for treating chronic fatigue syndrome (CFS). See: Marshall Protocol.

Although I have not seen it myself the book Peter J. Hyde, Sunlight, Vitamin D and Prostate Cancer Risk (ISBN: 1-4010-8258-0) is recommended by the doctor and urologist of Christopher Morash. See [link]

Lisa Tseng (2003) "Controversies in Vitamin D Supplementation", Nutrition Bytes: Vol. 9: No. 1, Article 3. [link]. Recommends getting vitamin D from sunlight.

Dr. Mercola discusses Vitamin D and sunshine: [Vitamin D and Cancer] [Vitamin D Deficiency]

Kevin Cahill, Vitamin D and Prostate Cancer, October 13, 2006. [link]

Reihold Vieth, Prospects for Vitamin D Nutrition, Calgary, Oct 13, 2005. Fascinating one hour presentation by a key researcher in Vitamin D intended for a lay audience. [link]. Also see Vieth's 1999 paper [link] and comments [link] and [link].

National Institute of Health Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. [link]

North American Conference on UV, Vitamin D and Health, Key Messages, March 8, 2006. [link]. The "Key Messages" coming from this conference have been endorsed by: American Cancer Society, American College of Rheumatology, Canadian Cancer Society, Canadian Dermatology Association, Dietitians of Canada, National Council on Skin Cancer Prevention (US), Osteoporosis Canada and the World Health Organization Collaborative Centre for the Promotion of Sun Protection. Also see [link] which discusses the document and provides a [link] to the Canadian Cancer Society's comments.

MS-Direct Vitamin D papers collection. See Vitamin D section at this [link]. A collection of online Vitamin D papers organized by Ashton Embry for MS patients (but some are applicable to prostate cancer too).

Charles Myers, Beating Prostate Cancer: Hormonal Therapy & Diet, 2006, pages 149 - 159. Myers recommends 4000 IU per day based on Vieth's 1999 paper (see above).

2 comments:

Herb said...

Men using elevated doses of o/t/c cholecalciferol (Vit D3) are reported wide variations in serum 25(OH)D levels. This is being attributed to poor quality control in the products, but there is no substantiation. I have been unable to find a lab that could/would do assays on a series of products. Any suggestions?

The Palpable Prostate said...

Regarding your question about labs for vitamin D, this paper [PMID: 15240586] discusses a study into Vitamin D assays at multiple laboratories. The author's email address is in the abstract. Perhaps you could contact him and ask.