A high and low status of levels of serum vitamin D was defined as above or below 23 ng/mL (57.5 nmol/L). After adjusting for age, diet and body mass index, ovarian cancer cases were over three times as likely to have inadequate 25(OH)D3 levels compared with the controls.

Previous research has shown that vitamin D induces apoptosis in ovarian CA cell lines, ovarian cancer has been inhibited by vitamin D in animal studies and although studies are mixed–ovarian cancer rates appear to be higher in areas with less sun exposure.

Other research on vitamin D consistently observes that a long list of chronic diseases and cancers are associated with lower vitamin D status, with some showing risk reduction when levels are above 30 ng/mL, 40 ng/mL and even 50 ng/mL. Despite this large and growing body of evidence, the Institute of Medicine recently released its Dietary Reference Intakes for Calcium and Vitamin D based on a target level of 20 ng/mL and randomized controlled trials, rather than the cornucopia of observational studies. This resulted in recommended doses of 600-800 I.U. per day depending on age. As I stated in a January blog, it is too bad… that these observational studies were not considered, and once again, we may not have optimal prevention and risk reduction guidelines from our government agencies. Many if not most alternative minded practitioners are recommending a routine dosing of 2,000 I.U. of vitamin D per day, in individuals who do not have a history of kidney stones nor elevated serum calcium levels. However, most women will achieve a minimum serum level of 23 ng/mL (as stated in this current ovarian cancer prevention study) at doses of 600 I.U.-1,000 I.U. per day. A simple blood test will confirm. This would be a logical step in women with risk factors for ovarian cancer or a personal history of ovarian cancer.

Reference: Bakhru A, Mallinger JB, Buckanovich RJ, Griggs JJ. Casting light on 25-hydroxyvitamin D deficiency in ovarian cancer: a study from the NHANES. Gynecol Oncol 2010;119:314-8.

A committee of experts evaluated more than one thousand studies and reports as well as listening to testimony from scientists and others. This committee considered that studies about the health benefits beyond bone health were most often from studies that provided mixed results, inconclusive results, or were not from randomized controlled trials. Thus, these were not considered reliable. Their focus then was on the bone growth and bone maintenance data.

Their new Recommended Dietary Allowance (RDA) is now 600 IU per day for people ages 1 to 70 and 800 IU per day for those 71 and older. The old guidelines from 1997 were 200 IU per day through age 50, 400 IU per day for ages 51 to 70 and 600 IU per day for 71 and older. While I would consider these guidelines conservative to the extreme, (really a one year old and a 70 y.o. need the same amount????) they at least increased a new safe upper limit of 4,000 IU a day for those 9 years old and above, pregnant or not. The greatest concern I have with these guidelines is that they based their bone dosing guidelines on a target blood level of 20 ng/ml per day, rather than 30 ng/ml per day minimum published in most research about levels needed to suppress the parathyroid gland and avoid unnecessary bone loss.

Most practitioners and a studious group of consumers realize that there are scores of studies on other potential health benefits found in observational/epidemiological studies including colorectal cancer, breast cancer, select autoimmune disorders, cardiovascular disease and much more. It is too bad… that these were not considered, and once again, we may not have optimal prevention, risk reduction guidelines from our government agencies.

For a full list of the dosing guidelines by age group, gender, and pregnancy status, you can find these at www.iom.edu/vitamind

A recent study on vitamin D and breast cancer risk was published that once  again points the way to vitamin D as a safe and important strategy in lowering breast cancer risk. The study included about 6,500 women between the ages of 25 and 74. Approximately half the women were diagnosed with breast cancer and half were not. According to the study results, a vitamin D supplement intake greater than 400 IU/day compared with no vitamin D supplement intake, reduces the risk of breast cancer by about 25%. This Canadian population-based, case-control study also observed that there was no influence of calcium supplement intake and breast cancer risk.

Commentary: This is just one study in a growing list of research publications demonstrating that vitamin D deficiency is associated with an increased risk of breast cancer, and other studies demonstrating that raising one’s serum level of vitamin D can lower the risk of breast cancer and breast cancer recurrence. Included below, is an article I published in the Townsend Letter for Doctors. While perhaps a bit technical for the non medical reader, I think the message is clear enough: Vitamin D is associated with a lower risk of breast cancer with the optimal guide of a maintenance dose that would achieve a serum 25 hydroxyvitamin D level of > 52 ng/mL in order to have a 50% reduction in breast cancer incidence.

Here is the article in total:

The Vitamin D and breast cancer link: Understanding associations, prevention, intervention; Townsend Letter for Doctors and Patients; August/Sept 2010, Issue #325/326

Tori Hudson, N.D.

Vitamin D deficiency has been associated with the increased risk of several cancers, including breast cancer. Given that breast cancer is the most common cancer in women in the United States, efforts towards identifying modifiable risk factors, targets for prevention with any lifestyle modification or nutritional influence is especially appealing.

One of the initial observations suggesting the potential for vitamin D to reduce breast cancer risk and mortality was from ecologic studies where higher latitude and therefore lower UV light, was associated with increased breast cancer incidence and

mortality. [i], [ii] , [iii] Other early evidence came from in vitro studies of breast cancer cell lines showing antiproliferative and proapoptotic effects of 1,25(OH)₂ D. [iv], [v] , [vi]

Epidemiological evidence is limited but in the first National Health and Nutrition Examination survey Follow-Up Study, higher sun exposure or high dietary or supplemental vitamin D intake, while not statistically significant, was consistently observed as an association with a decreased risk for breast cancer.[vii] In the Nurses’ Health Study, a higher dietary intake or total intake of vitamin D including supplementation was significantly associated with a lower risk of premenopausal breast cancer.[viii] An updated study was done with a cohort in a case-control study nested within the Nurses’ Health Study. The relationship between plasma levels of 25 (OH)D and 1,25 (OH)₂ D and breast cancer was prospectively examined.[ix] Women in the highest quintile of 25(OH)D had a nonsignificant lower risk of breast cancer compared with those in the lowest quintile, when both metabolites were analyzed. The association was stronger in women ages 60 years and older, but still, results were not statistically significant. The authors concluded that high levels of 25(OH)D, and perhaps 1,25 (OH)₂ D may be modestly associated with a reduced risk of breast cancer. This association with low levels of serum D and higher risk of breast cancer was very significant in a previous study, where women in the lowest quartile of serum 1,25(OH)₂D had a risk of breast cancer 5 times higher than those in the highest quartile.[x]

This suggestive evidence led to a population-based case-control study in Ontario, Canada.[xi] Women with invasive breast cancer diagnoses and women without breast cancer were identified and telephone interviews were completed for 972 cases and 1,135 controls. A reduced risk of breast cancer was associated with increasing sun exposure for girls aged 10-19 in those with the highest quartile of outdoor activities versus the lowest. A breast cancer reduced risk was also associated with cod liver oil use and > 10 glasses of milk per week vs none. The associations were weaker for women ages 20 to 29 and there was no evidence of an association for ages 45 to 54. In this study, it appears that vitamin D could be associated with a lowered risk of breast cancer, but particularly in ages when the breasts are developing.

Two calcium and vitamin D studies have not shown any relationship. The relationship between vitamin D and breast cancer was prospectively assessed among 10,000 premenopausal and 20,000 postmenopausal women who were enrolled in the Women’s Health Study.[xii] Intake of calcium and vitamin D was determined from self-reported questionnaires about diet and vitamin use.

During an average follow-up of 10 years, the overall incidence of invasive breast cancer was 2.6% among premenopausal women and 3.6% among postmenopausal women. Among premenopausal women, the hazard ratio for developing breast cancer was 0.61 for women in the highest versus lowest quintiles of calcium use and 0.65 for vitamin D intake. No benefit was seen for these nutrient intakes and breast cancer risk in postmenopausal women.

Another calcium plus vitamin D study was conducted, but in this study, postmenopausal women in the Women’s Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D daily, or placebo, for an average of 7.0 years. [xiii] While this was primarily a study to determine the effects of supplements on hip fracture incidence, invasive breast cancer was a secondary outcome. The incidence of invasive breast cancer was similar in the supplement vs placebo group. The results of this study were such that calcium and 400 IU of vitamin D supplementation per day did not reduce the incidence of invasive breast cancer in postmenopausal women, and serum 25-hydroxyvitamin D levels were not associated with breast cancer risk.

The Long Island Breast Cancer Study Project was conducted to investigate environmental factors associated with breast cancer risk. [xiv] Blood samples and data were collected from this study, to examine the relationship of plasma 25-OHD levels with breast cancer risk. Plasma 25-OHD was inversely associated with breast cancer risk. Compared with women with a vitamin D deficiency, defined as a serum 25-OHD level < 20 ng/mL, levels above 40 ng/mL were associated with a decreased breast cancer risk, and was greater in postmenopausal women, and independent of tumor hormone receptor status.

Another important study of Long Island women was a population-based case-control study where blood samples were obtained from 1,026 incident breast cancer cases and 1,075 population-based controls.[xv] Compared with women with a vitamin D deficiency, that is a serum level of 25-OHD, < 20 ng/mL, levels above 40 ng/mL were associated with a decreased risk of breast cancer, and the risk reduction was greater in postmenopausal women, nor did the effect vary according to tumor hormone receptor status.

Women with a current or past history of breast cancer might also take note of the influence of vitamin D and their breast cancer recurrence rate and mortality. Low 1,25 (OH)₂D levels have been associated with a faster progression of metastatic breast cancer.[xvi] The results of the prognostic effects of 25-hydroxyvitamin D levels in women with early stage breast cancers is one of the most frequent strategies I employ in breast cancer prevention and in reducing the risk of breast cancer recurrence. This prospective study of women with early breast cancers analyzed blood levels of vitamin D. [xvii] Vitamin D levels were deficient (< 50 nmol/L) in 37.5% of women, insufficient in (50 to 72 nmol/L) in 38.5% and sufficient (> 72 nmol/L) in only 24.0% of women. Women with vitamin D deficiency had an increased risk of distant recurrence and death compared with those with vitamin D sufficiency. One of the errors that many clinicians make however when reading a study like this is confusing the lab values of nmol/L with ng/mL. Most laboratories report in ng/mL. It should be noted that 75 nmol/L is equivalent to 30 ng/mL. This study then reports that sufficiency, and a better outcome, is associated with a serum Vitamin D level of 30 ng/mL. A more rigorous standard for serum levels and breast cancer risk reduction was proposed by combining data from observational studies.[xviii] The first visible increment in prevention of breast cancer was evident with serum 25 OHD levels > 32 ng/mL. In a paper analyzing combined data from several studies on colon, ovary and breast cancer, the authors determined that prevention of 30% of breast cancer incidence could be achieved if one sustained blood levels > 42 ng/mL and they projected that a 50% reduction could occur by lifelong maintenance of serum 25 OHD levels > 52 ng/mL.[xix] They estimated that the first meaningful increment of breast cancer prevention would required a minimum of 2,000 IU/day. It is this serum level of > 52 ng/mL that I have targeted as the optimal prevention dose I utilize in my practice.

Vitamin D food/supplement intake and sufficient sun exposure are the major factors that determine serum 25 OHD levels. Several factors influence the serum increases in response to vitamin D supplementation, including body mass index (BMI) with smaller responses in individuals with a high BMI compared to those with a normal BMI.[xx], [xxi] Estrogen therapy increases serum 25 OHD levels but does not alter the serum 25 OHD response to vitamin D supplementation.[xxii] Likewise, while serum D levels decline with aging, the response to a dose of supplemental Vitamin D is not affected by aging. [xxiii]

The average increment responses to 100 I.U. per day of vitamin D supplementation varies from an increase of 1.1 ng/mL serum 25 OHD at low starting serum D levels to 0.7 ng/mL at higher or near optimal starting serum 25 OHD levels. [xxiv] The average vitamin D requirement for older adults needed to reach a serum 25 OHD levels of 30 ng/mL is 800 to 1,000 I.U. per day. Higher doses may be needed in individuals who are obese, are homebound, have malabsorption, and are dark skinned individuals. Due to declining serum levels with aging, higher doses are needed for most older adults in order to maintain 30 ng/mL. Vitamin D dosing in order to reach > 52 ng/mL requires individual assessment/testing, and follow-up testing, generally at 3 month intervals until the desired serum level is reached. A maintenance dose would then be determined, based on the desired serum level, and as I have asserted, I would recommend a 25 OHD level of > 52 ng/mL in order to have a 50% reduction in breast cancer incidence.

[i] Gorham E, Garland F, Garland C. Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 1990;19:820-824.

[ii] Garland F, Garland C, Gorhan E, Young J. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 1990; 19:614-22.

[iii] Grant W. An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer 2002; 94:272-281.

[iv] Bortman P, Folgueira M, Katayama M, et al. Antiproliferative effects of 1,25-dihydroxymitamin D3 on breast cells: a mini review. Braz J Med Biol Res 2002;35:1-9.

[v] Coston K, Hansen C. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 2002;9:45-59.

[vi] Welsh J. Vitamin D and breast cancer. Insights from animal models. Am J Clin Nutr 2004;80:1721-4S.

[vii] John E, Schwartz G, Dreon D, Koo J. Vitamin D and breast cancer risk: the NHANES I Epidemiologic follow-up study, 1971-1975 to 1992. National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 1999;8:399-406.

[viii] Shin M, Holmes M, Hankinson S, et al. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. H Natl Cancer Inst 2002;94:1301-1311.

[ix] Bertone-Johnson E, Chen W, Holick M, et al. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1991-1997.

[x] Janowsky E, Lester G, Weinberg C, et al. Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk. Public Health Nutr. 1999;2(3):283-291.

[xi] Knight J, Lesosky M, Barnett H, et al. Vitamin D an reduced risk of breast cancer: A population-based case-control study. Cancer Epidemiol biomarkers Prev 2007;16(3):422-499.

[xii] Lin J et al. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007, May 28; 167(10):1050-1059.

[xiii] Chlebowski R, Johnson K, Kooperberg C, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2007;100:1581-1591.

[xiv] Gammon M, Neugut A, Santella R, et al. The Long Island Breast Cancer Study Project : description of a multi-institutional collaboration to identify environmental risk factors for breast cancer. Breast Cancer Res Treat 2002;74:235-254.

[xv] Crew K, Gammon M, Steck S, et al. Association between plasma 25-hydroxyvitamin D and breast cancer risk. Cancer Prev Res 2009;2(6):598-604.

[xvi] Mawer E, Walls J, Howell A, et al. Serum 1,25-dihydroxyvitamin D may be related inversely to disease activity in breast cancer patients with bone metastases. J Clin Endocrinol Metab. 1997;82:118-122.

[xvii] Goodwin P, Ennis M, Pritchard K, et al. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clinical Oncology 2009;27(23):3757-3763.

[xviii] Garland C, Gorham E, Mohr S, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103:708-711.

[xix] Garland C, Grant W, Mohr S, et al. What is the dose-response relationship between vitamin D and cancer risk? Nutrition Reviews 2007;65(8):S91-S95.

[xx] Wortsman J, Matsuoka L, Chen T, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:690-693.

[xxi] Blum M, Dallal G, Dawson-Hughes B. Body size and serum 25 hydroxyvitamin D response to oral supplements in healthy older adults. J Am Coll Nutr 2000;27:274-279.

[xxii] Harris S, Dawson-Hughes B. The association of oral contraceptive use with plasma 25-hydroxyvitamin D levels. J Am Coll Nutr 1998;17:282-284.

[xxiii] Harris S, Dawson-Hughes B. Plasma vitamin D and 25OHD responses of young and old men to supplementation with vitamin D3. J Am Coll Nutr 2002;21:357-362.

[xxiv] Heaney R, Davies K, Chen T, Holick M, Barger-Lux M. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2000; 77:204-210.

The average age was 50 and the average vitamin D levels was 58.1 nmol/L. Vitamin D levels were deficient (<50 nmol/L) in 192 women, insufficient (50 to 72 nmol/L) in 197 women and sufficient (> 72 nmol/L in 123 women. The average follow-up was 11.6 years with 116 women having distant recurrences and 106 women who died. Vitamin D levels were significantly lower in women with high grade tumors. Those women with vitamin D deficiency had an increased risk of distant recurrence and of dying, compared with those women who had sufficient serum vitamin D levels.

Commentary: This study is one more reason to test vitamin D levels- I would recommend it for all current or past breast cancer patients. In terms of using vitamin D levels to determine the initial risk for breast cancer, the evidence has been mixed, with some showing an association between latitude and risk of breast cancer, some showing an inverse relationship between vitamin D intake and breast density (a strong risk factor for breast cancer), but other studies showing vitamin D intake or blood levels of vitamin D inconsistently related to risk/incidence.

There have been some other attempts to use vitamin D levels as a prognostic indicator for breast cancer and mortality. Low vitamin D levels have been associated with increased breast cancer mortality and have also been shown to be significantly lower in women with locally advanced or metastatic disease compared with those women who have early breast cancers. Taking a vitamin D supplement to increase blood levels of vitamin D is one of the least expensive, safe strategies to reduce the risk of recurrence of breast cancer, as stated in this current study. For the rest of us… the research is full of good news about vitamin D and our health with studies demonstrating that higher blood levels of vitamin D is associated with lower rates of heart disease, ovarian cancer, multiple sclerosis, osteoarthritis and rheumatoid arthritis, bacterial vaginosis, and as mentioned, breast cancer.

It should be noted that the current studies, and in fact many studies, report vitamin D levels in the units of nmol/L. Other studies report ng/ml. This is a very important difference. It is important to compare one’s lab unit results for vitamin D levels with the proper target number and unit used. For reference, 75 nmol/L is equal to 30 ng/mL. In the current study, those women who had a vitamin D deficiency and reported as < 50 nmol/L would be equivalent to < 20 ng/ml.

References

Goodwin P, Ennis M, Pritchard K, et al. Prognostic effects of 25hydroxyvitamin D levels in early breast cancer. J Clinical Oncology 2009;27(23): 3757-3763

Peer-reviewed research studies were located in various data-bases searching for studies investigating vitamin D and depression, seasonal affective disorder, PMS, postpartum depression, perinatal depression, depressive disorder or mood disorder in women. Eleven studies were initially identified, but five were eliminated because they did not meet the inclusion criteria. Of these six studies, four reported significant results showing an association between low serum 25 (OH) D levels and symptoms of a mood disorder, SAD, major depressive disorder, or PMS. One study of major depression and one on SAD did not report an association. Only one of the four positive studies was a randomized controlled trial.

Vitamin D receptors are involved in the regulation of glucocorticoid signaling and dysfunctional glucocorticoid signaling and increased glucocorticoids have been implicated in major depressive disorder. Other biochemical mechanisms may also exist, associating vitamin D with mood disorders.

I look forward to more research on specific mood disorders in women and vitamin D levels.

References:

Murphy P, Wagner C. Vitamin D and mood disorders among women: an integrative review. J Midwifery Women’s Health 2008;53:440-446.

The results of this study suggest that a moderate to severe vitamin D deficiency is a risk factor for developing cardiovascular disease.  One would hope that treatment of vitamin D deficiency with vitamin D supplementation or adequate exposure to sunlight could reduce that risk.  While a randomized intervention trial would be needed to assess vitamin D supplementation as a treatment strategy, we do have other positive evidence showing vitamin D supplementation reducing blood pressure, ventricular hypertrophy and inflammatory cytokines.
References

Want T, Pencina M, Booth S, et al.  Vitamin D deficiency and risk of cardiovascular disease.  Circulation. 2008; 117: 503-511.

Commentary

This randomized, double-blind, placebo-controlled trial of daily supplementation of 1000 mg of elemental calcium with 400 IU vitamin D3 had no effect on the incidence of breast cancer. Some observational studies have demonstrated an association between higher calcium and vitamin D intake and reductions in breast cancer risk in postmenopausal women, while others have not. Studies in postmenopausal women have also been mixed in showing an association with lowered breast cancer risk in those with higher serum levels of 25-hydroxyvitamin D. Several thoughts regarding these mixed results are worth considering: 1) Different thresholds of serum 25-hydroxyvitamin D are used to assess associations and it may be that a higher threshold (52 nmol/L says some research; 75 nmol/L says other research) is needed to show an association. 2) Higher doses of vitamin D may be needed to demonstrate consistent results. 3) The doses of vitamin D used in different trials are not consistent. 4) The seven year duration of the current study may be insufficient given the latency of breast cancer. 5) Results may be confounded by lean women vs. overweight or obese women, recreational activity and sunlight exposure.

Given the wide variety of preventive effects of vitamin D supplementation, the multiple disease reduction benefits associated with higher serum levels, and the selected benefits on intervention with supplementation, for now, I will continue to be assertive in vitamin D dosing. The list of benefits and potential benefits spans so many diseases (heart disease, hypertension, peripheral vascular disease, osteoarthritis, osteoporosis, fractures, autoimmune diseases, depression, insulin resistance, ovarian cancer, breast cancer, colon cancer), that it remains compelling to recommend one of the most economical and safe supplements currently available.

References

• Chlebowski R, Johnson K, Kooperberg C, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2008 100: 1561.