A systematic literature review of vitamin D and ovarian cancer

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systematic literature review of vitamin D and ovarian cancerinda S. Cook, PhD; Heather K. Neilson, MSc; Diane L. Lorenzetti, MLS; Robert C. Lee, MSc

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BJECTIVE: We assessed the evidence supporting a reduction in riskor ovarian cancer occurrence or mortality with greater vitamin Dxposures.

TUDY DESIGN: This review followed standard guidelines for system-tic literature reviews. The diverse study designs precluded a quantita-ive metaanalysis. Therefore studies are summarized via tables and ab-tracted information.

ESULTS: Approximately half of the ecologic and case-control studieseported reductions in incidence or mortality with increasing geographic

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0.e1 American Journal of Obstetrics & Gynecology JULY 2010

amin D, whereas the other half reported null associations. The cohorttudies reported no overall risk reduction with increasing dietary/sup-lement consumption of vitamin D or with plasma levels of vitamin Drior to diagnosis, although vitamin D intakes were relatively low in alltudies.

ONCLUSION: There is no consistent or strong evidence to support thelaim made in numerous review articles that vitamin D exposures re-uce the risk for ovarian cancer occurrence or mortality.

ey words: ovarian neoplasms, sunlight, systematic review,
atitude, solar radiation levels, or dietary/supplement consumption of vi- ultraviolet radiation, vitamin D
ite this article as: Cook LS, Neilson HK, Lorenzetti DL, et al. A systematic literature review of vitamin D and ovarian cancer. Am J Obstet Gynecol

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itamin D (representing both D2

and D3) is more properly viewed ashormone rather than a vitamin. Hu-an beings obtain vitamin D via 2

ources: ultraviolet (UV)-B radiation inunlight that converts 7-dehydrocholes-erol to vitamin D3 in skin, and ingestionf vitamin D (D2 or D3) in food and sup-lements.1 Some fish and fish liver oilsontain vitamin D3, although smallmounts are also found in beef liver,

rom the Division of Epidemiology andiostatistics, Department of Internaledicine, University of New Mexico,

lbuquerque, NM (Dr Cook), and theepartment of Community Health Sciences,niversity of Calgary (Dr Cook, Msorenzetti, and Mr Lee), Alberta Healthervices (Dr Cook and Ms Neilson), Calgary,nd the Institute of Health Economics,dmonton (Ms Lorenzetti), Alberta, Canada.r Lee is currently with the Department of

mergency Medicine, University of Newexico, Albuquerque, NM.

eceived July 25, 2009; revised Oct. 7, 2009;ccepted Jan. 20, 2010.

eprints not available from the authors.

r Cook held a Canada Research Chair andeceived career award funding from the Albertaeritage Foundation for Medical Research

hrough 2007.

002-9378/$36.002010 Mosby, Inc. All rights reserved.

heese, and egg yolks.2 Fortified foods,uch as milk, margarine, yogurt, cereal,nd orange juice provide most of the vi-amin D in the US diet.2 Once in the cir-ulation, vitamin D (either D2 or D3) isonverted to 25-hydroxyvitamin D (25-OH)D) in the liver and then further me-abolized to 1,25-dihydroxyvitamin D1,25-(OH)2D) in the kidney and otherissues in the body. There are biologicaleasons to suspect that the active form,,25-(OH)2D,3 may be related to ovarianancer incidence and mortality. For ex-mple, the vitamin D nuclear receptor,hich mediates the effect of 1,25-

OH)2D3, is found in human ovarianumor specimens and cell lines.4-6 Addi-ionally, 1,25-(OH)2D3 inhibits cell pro-iferation in ovarian cancer cell lines5,7

nd induces apoptosis.8

If indeed vitamin D can reduce ovar-an cancer occurrence and mortality,hen it represents a promising modifi-ble risk factor for ovarian cancer. How-ver, a recent report from the Interna-ional Agency for Research on Cancer onitamin D and cancer did not evaluatevarian cancer because of sparse infor-ation from primary research relative to

hat for other cancers such as colorectal,rostate, and breast cancers.9 Despitehis, numerous review articles state thatitamin D reduces ovarian cancer occur-

-15 Therefore, we c

onducted a systematic review to assesshe strength of the evidence with regardo the claim that higher (vs lower) vita-

in D-related exposures are associatedith a reduction in the risk for ovarian

ancer occurrence or mortality.

ATERIALS AND METHODSearch strategyhis review followed the guidelines for

ystematic reviews of observational stud-es.16 Ten electronic databases includingltHealthWatch, AMED, Biological Ab-

tracts, BIOSIS, CINAHL, Cochrane Li-rary, EMBASE, MEDLINE, Proquestissertations, and the University ofork’s Health Technology Assessmentatabase, plus select international gov-rnment World Wide Web sites, wereearched up to July 2008 to identify rele-ant articles published in English orrench. Databases and World Wide Webites were searched using the followingerms, both as text words and, as appro-riate, Medical Subject Headings orquivalent subject heading/thesauruserms: (ovary or ovaries or ovarian) andcancer* or carcinoma* or carcinogen*r neoplasm* or tumor* or tumour*)nd (vitamin D or 1,25-dihydroxyvita-in D or 25-hydroxyvitamin D or lati-

ude or solar or sun or sunlight or sunshiner uv or uvb or uv-b or ultraviolet or cal-
ium or dairy or margarine* or milk or cod

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iver oil* or fish oil* or halibut or herring orackerel or oyster* or salmon or sardine*

r swordfish or tuna).The complete search strategy is available

n request. Searches were supplementedy scanning bibliographies of all articlesndergoing full-text review and review ar-

icles, and excluded articles flagged for aeference check. In total, the searches iden-ified 2061 unique citations (Figure).

creening of abstracts for eligibilitybstracts/titles identified from the

earch were screened for eligibility by 2eviewers (L.S.C. and H.K.N.). The 2 re-iewers agreed on inclusion and exclu-ion for 96.8% of the abstracts/titleskappa � 0.86). The remaining discrep-ncies were discussed and consensuseached in every instance. Abstracts werehosen for full-text review if they re-orted original data including: (1) vita-

FIGUREProgress through systematic review

2061 abstracts/titles identifie

277 identified for full text article r

Titles and abstracts

264 articles identified from database7 articles identified by scanning bibli

20 full text articles included

Full text articles

Data abstraction

ook. Vitamin D and ovarian cancer literature review. Am J

in D exposure or proxies (ie, vitamin D t

easured directly; dietary exposure [in-luding supplements]; vitamin D in bio-ogical samples; solar irradiation mea-ures; geographic location [eg, latitude];nd/or relevant occupational groups [eg,ndoor vs outdoor workers]); and (2)varian cancer incidence, mortality,nd/or survival. To ensure we capturedll original data, we retained abstractsnd titles that met these criteria even ifhey appeared to be review articles. Welso retained articles whose relevanceas uncertain due to lack of published

bstracts.A diagnosis of nonmelanoma skin

ancer (NMSC) (as a proxy for sun ex-osure) was not 1 of the inclusion crite-ia. NMSCs are most likely underre-orted because they can be treated byhysicians or outpatient clinics withoutistologic confirmation. Additionally,

eval

1784 excludedMet inclusion criteria for - 34 animal or in vitro s - 4 case study of single - 4 benign neoplasms on119 met only 1 inclusion vitamin D) 1572 did not meet either i51 were single page articl relevant

13 articles could not be lo

arch + aphies 251 excluded

1 animal or in vitro study10 met inclusion criteria b ovarian cancer and vita147 met only 1 inclusion vitamin D) 48 did not meet either inc45 were summaries in new articles already identif

et Gynecol 2010.

he majority of NMSCs are basal cell car- i

JULY 2010 Ameri

inomas for which the pattern of inter-ittent exposure and sunburn may beore important than chronic or cumu-

ative exposure.17 Thus, a priori, we con-idered NMSC a poor proxy for cumula-ive sun exposure, which may in turn be

proxy for cumulative vitamin Dxposure.

ull-text review of articlesll the authors developed the full-text

creening tool and all participated in aest screening on a random sample of 10rticles to ensure the reproducibility ofhe full-text screening tool. Agreementas 100%. One reviewer (L.S.C.) then

onducted a full-text article screen on71 articles. A total of 251 articles werexcluded based on a priori criteria (Fig-re). Articles that employed the resultsf previously conducted ecologic studieso estimate potential reductions in ovar-

rian cancer and vitamin D, but: y/review only ividual

eria (either ovarian cancer or

usion criteria no abstract, title was not

ed

iew only statistical analyses did not assess n D directly eria (either ovarian cancer or

ion criteria etters or review articles citing and included

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ere excluded because the goal of thiseview was to assess the primary evi-ence for an association between vita-in D–related measures and ovarian

ancer incidence and mortality. Relevantnformation was abstracted from the re-

aining 20 articles. These articles re-ected ecologic, case-control, and co-ort studies. No randomized controlledrials were identified. One ecologictudy19 used the same mortality data andV-B irradiance information as in a pre-

ious study,20 with a slightly differentnalysis; thus only the later analysis19

as included in the review.

ata abstractionne reviewer (L.S.C.) completed all data

TABLE 1Ecologic studies included in review

Citation LocationOvaand

Pinto21 United States Mor

...................................................................................................................

Decarli and LaVecchia22

Italy Mor

...................................................................................................................

Lefkowitz andGarland23

United States Mor

...................................................................................................................

Mizoue24 Japan Mor

...................................................................................................................

Grant25 Multiple countries ● Mra

● 1d

...................................................................................................................

Grant26 Spain Mor...................................................................................................................

Boscoe andSchymura27

United States IncidMor

...................................................................................................................

Garland et al28 Multiple countries Incid

...................................................................................................................

Waltz andChodick29

Multiple countries Incid

...................................................................................................................

Grant andGarland19

United States Mor197

...................................................................................................................

NASA, National Aeronautics and Space Administration; TOMS

Cook. Vitamin D and ovarian cancer literature review. Am

bstractions. The following information r

0.e3 American Journal of Obstetrics & Gynecolog

as abstracted from all studies: study de-ign; geographic location; time period;ource and number of participants; race/thnic composition; age composition;easure of ovarian cancer (incidence,ortality, survival); ovarian cancer be-

avior (invasive vs borderline); measurer proxy for vitamin D (food, supple-ents, food plus supplements, latitude,

unlight, UV-B); time frame of measure-ent; and outcomes (odds ratios [OR],

elative risks [RR], correlations).

nalysishe various study designs and analyticalethods represented in the reviewed

tudies precluded a quantitative meta-nalysis. Therefore, studies are summa-

cancer measurelendar time Vitamin D proxy measu

y, 1950-1978 Latitude and latitude/longby county

.........................................................................................................................

y, 1969-1978 Latitude, set value for 20administrative regions

.........................................................................................................................

y, 1979-1988 Average sunlight (cal/cmmain city per county, ave10 y (calendar years not

.........................................................................................................................

y, 2000 Average annual hours ofradiation for central cityprefecture (kW h/d), 196Japan Meteorological Ag

.........................................................................................................................

lity/incidence2002d 5-y survival,osed 1990-1994

Latitude, set value per cocountries

.........................................................................................................................

y, 1978-1992 Latitude set value per pr.........................................................................................................................

ce, 1998-2002y, 1993-2002

UV-B from NASA TOMS,monthly average per cou

.........................................................................................................................

ce, 2002 ● Latitude, set value per● UV-B, top of atmosphe

equinox.........................................................................................................................

ce, 1993-1997 UV-B data from Robertsometers

.........................................................................................................................

y, 1950-1969 and994

● UV-B from NASA TOMS1992, per state

● UV-B from 19 USDA grbased UV-B monitoringaverage of 1970-1994

.........................................................................................................................

l Ozone Mapping Spectrometer; USDA, US Department of Agricu

bstet Gynecol 2010.

ized via tables and written descriptions. l

y JULY 2010

ESULTScologic studiesen ecologic studies reported original

esults on the relationship between lati-ude or similar measures of UV-B irradi-nce and ovarian cancer mortality19,21-27

r incidence27-29 (Table 1). A commonuestion addressed was whether ovarianancer mortality increased with increas-ng latitude from the equator. Two stud-es noted that ovarian cancer mortalityncreased with latitude using 17 coun-ries25 or within Italy alone,22 whereas 2thers within the United States21 andpain26 did not. Another question washether mortality decreased with in-

reasing UV-B exposure or average sun-

Increasing latitude ordecreasing UV-B/sunlightassociated with increasingmortality or incidence?

de index No

..................................................................................................................

lian Yes, but level of significancenot reported

..................................................................................................................

fore overcified)

Yes, P value � .001

..................................................................................................................

arach990,y

No

..................................................................................................................

ry, 17 Yes, P value � .01

..................................................................................................................

ce No..................................................................................................................

6-2003, Authors reported “no evidence”

..................................................................................................................

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..................................................................................................................

uly

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..................................................................................................................

; UV, ultraviolet.

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ight/solar irradiance. Two studies re-

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orted that increasing UV-B exposure inhe United States19 or increased sunlightn the United States23 was significantlyssociated with decreasing ovarian can-er mortality, whereas 2 other studies, 1f solar irradiance in Japan24 and 1 ofV-B exposure in the United States,27

ound no evidence of an inverse associa-ion. For incidence, 2 studies found novidence that ovarian cancer incidenceecreased with increasing UV-B expo-ure in the United States or across theorld,27,29 whereas another worldwide

nalysis reported that incidence in-reased with increasing latitude andecreased with increasing UV-Bxposure.28

Thus, there have been inconsistentndings in ecologic studies of incidencer mortality. Half of the studies foundhat ovarian cancer mortality or inci-ence increases with increasing latituder decreasing solar irradiance, while thether half did not. There was much vari-tion in analytic methods and adjust-ent for other ecologic variables ranging

rom lifestyle variables such as popula-ion estimates of average number oflcoholic drinks in the last 30 days27 totmospheric variables such as strato-pheric ozone thickness,23,28 but the pat-ern of results did not align with the typef analysis or the extent of adjustment.

ase-control studiestotal of 6 case-control studies met the

nclusion criteria; 1 evaluated ovarianancer mortality30 and the other 5 eval-ated incidence31-35 (Table 2). The mor-

ality study30 reported that being ex-osed to high vs low annual solaradiation (based on death certificatesnd state of residence at death) was asso-iated with a lower risk of ovarian cancereath (odds ratio [OR], 0.84; 95% confi-ence interval [CI], 0.81– 0.88), al-hough the risk for women whose usualccupation listed on the death certificate

nvolved outdoor work was similar tohat of indoor workers (OR, 0.94; 95%I, 0.75–1.17 and OR, 1.12; 95% CI,.88 –1.41, respectively). The ecologicssignment of low, medium, and highnnual mean daily solar radiation in thetate of residence at death makes it diffi-
ult to directly compare this study to the e
ther case-control studies with individ-al level information (summarizedelow).The 5 case-control studies that evalu-

ted incident cancer all assessed someomponent of diet relevant to vitamin D.ne study found that incidence in thoseith daily consumption of cod liver oil

or at least 1 month in the 5 years beforeiagnosis was similar to those witho consumption (OR, 1.2; 95% CI, 0.45–.90).32 For dietary consumption of vita-in D, 2 studies noted either a border-

ine reduction in risk (OR, 0.70; 95% CI,.6 –1.0)33 or a significant reduction inisk (OR, 0.43; 95% CI, 0.23– 0.80)34 inhe highest vs lowest categories of intake.wo other studies that assessed total vi-

amin D (diet plus supplements) did notnd a reduction in risk in the highest vs

owest intake categories (OR, 0.99; 95%I, 0.65–1.5231 and OR, 0.84; 95% CI,.57–1.2335).In summary, several case-control

tudies found a reduced risk with dietaryonsumption of vitamin D,33,34 but sev-ral others that included supplement useith greater total estimated intakes of vi-

amin D did not find any reduction.31,35

hus, case-control studies showed noonsistent pattern of results with respecto dietary and/or supplement intakes ofitamin D and ovarian cancer risk.

ohort studies or nested case-controltudies within cohortsour cohort studies or nested case-con-rol studies within cohorts met our in-lusion criteria, including 2 individualohort studies,36,37 1 nested case-controltudy within 3 cohorts,38 and 1 pooledohort study of 9 cohorts10 (Table 3).he pooled study10 is not independent of

he other studies36-38 because these stud-es were included in the pooled analysis.iven the additional studies in theooled analysis, and the difference in ex-osure variables between the study byworoger et al38 (plasma levels of vita-in D) and the pooled analysis10 (vita-in D dietary intake and total intake),

he overlap in study data seemed moder-te. Nonetheless, the lack of indepen-ence between studies should be consid-
red in the interpretation of this review. t
JULY 2010 Ameri

Two of the cohort studies and theooled cohort study10 addressed vitamin

dietary intake and supplement use;omen with the highest intakes had a

imilar risk for ovarian cancer as womenith the lower intakes (eg, risk ratio

RR], 1.12; 95% CI, 0.90 –1.38 for totalntake of �500 IU per day relative to

100 IU per day10). Similarly, no reduc-ion in risk was noted in the highest vshe lowest quartile of plasma 25-(OH)D3

RR, 0.83; 95% CI, 0.49 –1.39 and RR,.14; 95% CI, 0.70 –1.85, respectively).38

owever, there was a significant inversessociation between 25-(OH)D3 and riskmong women with a body mass index

25 kg/m2 (RR, 0.39; 95% CI, 0.16 –.93 for the highest vs lowest quartile of5-(OH)D3 levels).Overall, the cohort studies provide lit-

le support for the hypothesis that di-tary/supplement intakes of vitamin Deduce the risk for ovarian cancer. How-ver, the cohort study evaluating plasmaitamin D levels38 (representing bothV-B and dietary/supplemental vitaminexposures) did report a reduced risk

ith increasing 25-(OH)D3 levels amongeavier women.

OMMENTe found no consistent or strong evi-

ence to support the claim made in nu-erous published review articles that vi-

amin D exposures, whether measuredhrough circulating levels, dietary/sup-lement intake, or proxy measures, aressociated with a reduced risk for ovar-an cancer incidence or mortality. This isn area worthy of further primary re-earch because of the biologic plausibil-ty of a connection between vitamin Dnd ovarian cancer and the limitations ofhe studies included in this review (dis-ussed below). Nonetheless, based onhe current evidence, it is premature to

ake any definitive claims for or againsthe role of vitamin D in ovarian cancerncidence or mortality.

Our systematic review has limitations.e searched for all relevant articles in

nglish and French, and thus did not in-lude articles in other languages. We alsoould not locate 13 articles. However,
hese articles were published in lay health

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7

agazines, and given that all other mag-zine articles we reviewed highlighted re-ults from studies that were already in-luded in our review, we are confidenthat we did not miss any additional pri-

ary studies. It is also possible that weissed some relevant articles due to our

eview criteria and process. For example,n additional cohort study39 assessed aumber of dietary factors, including vi-

amin D. Ovarian cancer risk did not

TABLE 2Case-control studies included in re

CitationNo. of cases,age in y

No. of controage in y

Based on mortality..........................................................................................................

Freedman et al30 n � 39,002ovariancancerdeathsa

Age�50, 8.8%50-69, 41.6%�70, 49.6%

n � 70,081deaths fromcauses otherthan ovariancancera

Age�50, 5.9%50-69, 24.8%�70, 69.3%

...................................................................................................................

Based on incidence..........................................................................................................

Cramer et al31 n � 549Age notstated

n � 516Age not stated

..........................................................................................................

Bertone et al32 n � 327Age�55, 27%55-74, 63%�74, 10%

n � 3129Age�55, 27%55-74, 63%�74, 10%

..........................................................................................................

Bidoli et al33 n � 1031Agemedian: 53range: 20–79

n � 2411Agemedian: 54range: 18–81

..........................................................................................................

Salazar-Martinezet al34



..........................................................................................................

Goodman et al35 n � 558Age�45, 23.3%45-64, 49.6%�64, 27.1%

n � 607Age�45, 24.6%45-64, 44.3%�64, 31.1%

...................................................................................................................

CI, confidence interval; NR, not reported; OR, odds ratio.a State of birth and state residence on death certificate had to


ary with increasing total (food plus n


upplements) vitamin D intake (RR,.97; 95% CI, 0.61–1.56 for �550 IU vs115 IU on average per day). As only

ositive findings were noted in the ab-tract of this article and not the nullesults of vitamin D, this article wasot identified in our search. It is possi-le that we missed other articles due toimilar omissions of null results in ab-tracts, but the inclusion of any addi-ional studies with null results would

wLocation, calendar timeControl source

Vitamin D exposureinformation Vita

.........................................................................................................................

United States, 24 states,1984-1995Control source: deathcertificates

State of residence atdeath assigned aslow, medium, or highannual mean dailysolar radiationUsual occupationfrom deathcertificate

StatresidLowMedHighOccuIndoMixeOutdFarm

.........................................................................................................................

.........................................................................................................................

Massachusetts, NewHampshire, 1992-1997Control source: random-digit dialing

Food frequencyquestionnaire, pastyear

Dietsuppintak�16163258387�58

.........................................................................................................................

Wisconsin,Massachusetts, 1991-1994Control source: licenseddrivers, Medicare

17 foods and vitaminsupplements, past5 y

CodNoYes

.........................................................................................................................

Italy: Pordenone andPadua Provinces, Milan,Latina, Naples, 1992-1999Control source: hospitals

78-item foodfrequencyquestionnaire, past2 y

Diet(IU/d12345

.........................................................................................................................

Mexico: South MexicoCity, 1995-1997Control source: medicalclinics

116-item foodfrequencyquestionnaire, pastyear

Diet(IU/d�21215�35

.........................................................................................................................

United States: Hawaiiand Los Angeles, CA,1993-1999Control source: Oahuwomen interviewed bythe Department of Health(Hawaii) andneighborhood sampling(Los Angeles, CA)

256-item foodfrequencyquestionnaire, pastyear

Dietsuppintak�15150282�46

.........................................................................................................................

he same.

bstet Gynecol 2010.

ot have changed our overall conclu- s

y JULY 2010

ions. It is also possible that some stud-es with null results were simply notublished, a well-known publicationias. We were also unable to conduct auantitative metaanalysis due to theariation in methods used in the stud-es included in this review. Nonethe-ess, the relatively small number oftudies included in the review made itossible to describe each in some de-ail, highlighting the heterogeneity and

D proxy OR (95% CI) Adjustment factors

..................................................................................................................

on

1.0referent0.90 (0.87–0.93)0.84 (0.81–0.88)1.0referent1.02 (0.94–1.10)0.94 (0.75–1.17)1.12 (0.88–1.41)

Age, race, occupationalphysical activity,socioeconomic status(based on deathcertificate information)

..................................................................................................................

..................................................................................................................

ndent/d)

1.0referent0.67NR0.70NR0.87NR0.99 (0.65–1.52)

Total calorie intake,age, site, parity, bodymass, oralcontraceptive use,family history ofbreast/ovarian/prostatecancer, tubal ligation,education, maritalstatus

..................................................................................................................

oil 1.0referent1.2 (0.45–2.90)

Age, state, parity, tuballigation, family historyof ovarian cancer

..................................................................................................................

takeintiles)

1.0referent0.80 (0.6–1.1)0.90 (0.7–1.2)0.90 (0.7–1.2)0.70 (0.6–1.0)

Age, study center,interview year,education, body mass,parity, oralcontraceptive use,occupational physicalactivity, energy intake

..................................................................................................................

take 1.0referent0.70 (0.40–1.24)0.43 (0.23–0.80)

Age, energy intake, livebirths, recent changesin weight, physicalactivity, diabetes

..................................................................................................................

ndent/d)

1.0referent0.98 (0.70–1.38)0.80 (0.56–1.14)0.84 (0.57–1.23)

Age, ethnicity, studycenter, education, oralcontraceptives, parity,tubal ligation, energyintake

..................................................................................................................

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id not exclude studies based on auality or validity index, because theisparate methods used in these stud-

es precluded a standard quality index.The primary studies included in this

eview also had limitations. While theesults of ecologic studies are useful for

TABLE 3Cohort studies included in review

CitationNo. of cases/cohortsize, age in ya Cohort so

Kushi etal36

139/29,083Age, 55-69

GeneralpopulationFU: 10 y

...................................................................................................................

Koralek etal37

146/31,925Mean age, 61.4b

29 breastscreeningin 27 US cFU: 245,4person-y

...................................................................................................................

Tworogeret al38

224/603c

Mean age, 56 (34-69) (NHS and NHS II)Mean age, 56 (45-73) (WHS)

NHS, NHSFU: N/A

...................................................................................................................

Genkingeret al10

1583/469,9271296/408,824Age not stated,depends on study

Pooled resfrom 9 orstudies deon analysFU: 7-22 ydependingcohort

...................................................................................................................

BMI, body mass index; CI, confidence interval; FU, follow-up;a At baseline; b Calculated by current authors from Table 1;37


enerating hypotheses concerning the fi

otential effects of UV-B or sunlightn ovarian cancer risk, it is unwise toake causal inferences from these

tudies. The most serious limitation ofhese studies is the well-known eco-ogic fallacy. This occurs when associ-tions for groups of individuals de-

e FUVitamin D exposureinformation Vitamin D measu

a126-item foodfrequencyquestionnaire, pastyear at baseline

Dietary intake (IU/�198.5198.5-325.0325.1-566.0�566.0

.........................................................................................................................

certers

62-item foodfrequencyquestionnaire, pastyear at baseline

Dietary intake(quartiles)1 (mean 57 IU/d)2 (mean 112 IU/d)3 (mean 163 IU/d)4 (mean 250 IU/d)Dietary andsupplement intake1 (mean 69 IU/d)2 (mean 143 IU/d)3 (mean 254 IU/d)4 (mean 615 IU/d)

.........................................................................................................................

HS Peripheral blood(plasma) at baseline(ie, blood draw)

25-hydroxyvitaminD (ng/mL) (quartile12341,25-dihydroxyvitamin D(pg/mL) (quartiles)1234

.........................................................................................................................

ding

Study-specific foodfrequencyquestionnaires, mostpast year at baseline

Dietary intake (IU/�100100-199.9200-299.9300-399.9400-499.9�500Dietary andsupplement intake(IU/d)�100100-199.9200-299.9300-399.9400-499.9�500

.........................................................................................................................

onapplicable; NHS, Nurses’ Health Study; RR, relative risk; WHS

ses/controls in nested case-control study within cohorts.

bstet Gynecol 2010.

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ountry, state, city) and an event (eg,iagnosis, death) are not the same ashose for individuals. Results fromcologic studies can often be provoca-ive, but they are a weak source of evi-ence and require confirmation fromtudies that address individuals, not

RR (95% CI) Adjustment factors

1.0referent1.26 (0.74–2.15)1.39 (0.83–2.36)1.37 (0.81–2.32)

Age, total energy intake,live births, age atmenopause, first-degreefamily ovarian cancerhistory, hysterectomy/unilateral oophorectomy,waist/hip ratio, physicalactivity, smoking,education

..................................................................................................................

1.0referent1.15 (0.74–1.79)0.73 (0.45–1.19)0.95 (0.60–1.51)1.0referent0.95 (0.55–1.62)0.97 (0.53–1.79)1.08 (0.63–1.87)

Age, menopausal status,parity, oralcontraceptive use,menopausal hormonetherapy (total intakeadditionally adjusted forcalcium intake, lactoseintake, and age atmenarche)

..................................................................................................................

1.0referent0.97 (0.61–1.52)1.20 (0.75–1.93)0.83 (0.49–1.39)1.0referent1.15 (0.71–1.85)1.25 (0.79–1.97)1.14 (0.70–1.85)

Menopausal hormonetherapy, BMI at blooddraw, parity, lactoseintake, duration of oralcontraceptive use,season of blood draw,interaction betweenstudy and duration oforal contraceptive use,and interaction betweenstudy and BMI at blooddraw

..................................................................................................................

1.0referent1.05 (0.90–1.23)1.10 (0.93–1.30)1.05 (0.83–1.33)1.56 (1.17–2.08)1.37 (0.78–2.40)1.0referent1.20 (0.97–1.48)1.26 (1.00–1.57)1.09 (0.79–1.51)1.27 (0.98–1.64)1.12 (0.90–1.38)

Age at menarche,menopausal status, oralcontraceptive use,menopausal hormonetherapy, parity, BMI,smoking, physicalactivity, and energyintake

..................................................................................................................

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7

In the particular case of ovarian cancernd vitamin D, the individual level stud-es do not add much clarity with regardo whether vitamin D exposures confer aeduction in risk for ovarian cancer. Theesults are mixed and, to our knowledge,one of these studies were designed topecifically assess all vitamin D expo-ures (UV-B, diet, and supplements) andvarian cancer risk. All but 1 of the inci-ent case-control and cohort studies as-essed dietary/supplement intake only. Its possible that circulating levels of vita-

in D derived from dietary sources, anderhaps from supplement sources, areegligible compared to those from sunxposure in some individuals, making itifficult to detect an association when as-essing dietary/supplement intake only.he limited range of intakes of vitamin D

n the studies may also be too low to seen effect. At best, the highest categoriesf dietary/supplement intakes barelyet the adequate intake (400-600 IU per

ay for the majority of women in thesetudies) as determined by the Institute of

edicine.2 Note that these recom-ended intake levels may be revised up-ard when the results of the current In-

titute of Medicine assessment andpdate of the Dietary Reference Intakes

or vitamin D and calcium are released inid-2010.40 Additionally, the dietary in-

akes were measured with food fre-uency questionnaires that have modestorrelations with serum or plasma levelitamin D41,42 and so the validity of thexposure assessments may be less thanptimal. As well, dietary intake was onlyeasured at 1 time period (eg, over the

ast year or the past 2 years) in thesetudies, and dietary habits may changever time (eg, a reduction in consump-ion of dairy products with increasingge).43,44 The limitations of the studiesuggest that the association between vi-amin D and ovarian cancer risk has noteen rigorously established.The strongest evidence comes from

he cohort study that assessed plasmaevels of vitamin D before ovarian canceriagnosis.38 This study did not find thatitamin D levels were associated with anlevated or reduced risk for ovarian can-er after controlling for a number of fac-
ors, including season of blood draw. In 1

ubgroup analyses, heavier womenbody mass index �25 kg/m2) had a re-uced risk with increasing vitamin D lev-ls; a finding that needs to be confirmedn other studies.

Future research on vitamin D andvarian cancer faces many challengesnd must address a wide spectrum ofuestions including: the most appropri-te time in ovarian cancer developmento assess vitamin D exposures (ie, close toiagnosis or in the distant past); the rel-tive contribution of sun exposure vsiet/supplements to risk; potential mod-

fication by other factors such as age,ody size, ethnicity and skin color, sunrotective behaviors, and calcium in-ake; standardized measurement of cir-ulating vitamin D across studies; andariation in the metabolism of vitamin Dhat may influence risk.

Given the weak level of evidence sup-orting vitamin D’s role in reducing theisk for ovarian cancer or ovarian cancerortality, it is puzzling that many review

rticles (and indeed background sectionsf other articles) make this claim.hether this is due to citation of only

tudies with positive results, selection ofubgroup analyses that show positive re-ults, inference of causality from ecologictudies, repetition of statements made inther articles, or other factors, is notlear. The possibility that vitamin D mayeduce ovarian cancer occurrence is in-riguing, however, and we fully supportrimary research in this area. A simple

ncrease in vitamin D exposure, if trulyssociated with lowered risk, would ben important intervention strategy foreducing ovarian cancer occurrence.his hypothesis, however, needs to be

ested with rigorous epidemiologictudies. f

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Documents

A systematic literature review of vitamin D and ovarian cancer