Milk consumption and prostate cancer

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http://www.cancerproject.org/survival/cancer_facts/prostate_dairy.php

Milk Consumption and Prostate Cancer

By Neal D. Barnard, M.D.

Abstract

Prostate cancer is one of the most common malignancies worldwide, with an

estimated

400,000 new cases diagnosed annually. Its incidence and mortality have been

associated

with milk or dairy product consumption in international and interregional

correlational

studies. As a result, case-control and cohort studies have further investigated

this

association and are described in this review. Of 12 case-control studies, six

found

significant associations, as did five of 11 cohort studies, with relative risk

of prostate

cancer among those with the most frequent dairy product consumption ranging

between

1.3 and 2.5, with evidence of a dose-response relationship. Mechanisms that may

explain

this association include the deleterious effect of high-calcium foods on vitamin

D balance,

the tendency of frequent dairy intake to increase serum insulin-like growth

factor I (IGF-I)

concentrations, and the effect of dairy products on testosterone concentration

or activity.

Introduction

Prostate cancer is the fourth most common malignancy among men worldwide, with

an

estimated 400,000 new cases diagnosed annually, accounting for 3.9 percent of

all new

cancer cases.1 Epidemiologic evidence strongly suggests that dietary factors

play a major

role in prostate cancer progression and mortality, with protective effects

associated with

consumption of fruit (particularly tomatoes), vitamin E, and selenium, and

increased risk

linked to dairy products, meat, and fat.2 Dairy product consumption has been

associated

with prostate cancer risk in divergent populations, and several studies have

investigated

mechanisms that may explain these findings. This review describes studies

reporting

prostate cancer risk in relation to milk or dairy products generally. It does

not include

studies reporting only intake of individual milk derivatives, such as butter, or

nutrients,

such as fat.

Correlational Studies

In international and interregional correlational studies, dairy product

consumption has

been consistently associated with prostate cancer mortality.3-7 The largest and

most

recent of these, based on World Health Organization mortality figures for

1985-1989 from

59 countries and United Nations food balance data for 1979-1981, reported a

strong

correlation between per capita milk consumption and prostate cancer mortality (r

= 0.78,

P<0.0001).7 A more geographically restricted study, conducted in 20 Italian

regions,

found a similar correlation between prostate cancer mortality and milk

consumption (r =

0.75, P <0.01).6

International correlational studies typically rely on food " disappearance " data,

which may

not accurately reflect intake, and are limited in their ability to control for

potential

confounders. They are also subject to variability in reporting practices,

although this is

less likely to influence mortality data than incidence figures. Some of the

weaknesses of

international correlational studies are avoided in case-control and cohort

studies. Case-

control studies compare the recalled diets of individuals with cancer with the

diets of

individuals without cancer who are similar in other relevant respects. Because

cases and

locally recruited controls are likely to have similar dietary patterns, the

sensitivity of such

studies is often limited. Cohort studies gather dietary information from healthy

volunteers

who are then followed over time.

Case-Control Studies

Six case-control studies in geographically diverse areas have reported

significantly

increased risk of prostate cancer (relative risk ranging from 1.5 to 2.5) for

those in the

highest categories of dairy product consumption, compared with lower consumption

levels

(Table 1).8-13 Four additional studies reported nonsignificant positive

associations, and

two found no association between dairy product consumption and prostate cancer

incidence.14-19

Two studies in northern Italy compared prostate cancer patients with hospital

controls,

finding increased risk of prostate cancer among those with the most frequent

milk

consumption.8-10 Similarly, a study at Roswell Park Memorial Institute in

Buffalo, N.Y.,

found an increased risk of prostate cancer with the daily consumption of three

or more

glasses of whole milk, compared with never drinking milk.9In Montevideo,

Uruguay, a

comparison of prostate cancer patients with hospital controls, most of whom had

other

forms of cancer, found an increased risk of prostate cancer associated with

drinking two

or more milk servings per day, compared with having less than one serving per

day.11 In

Örebro county, Sweden, men with prostate cancer were compared with controls

selected

from a population register. Higher dairy product consumption was associated with

increased relative risk of prostate cancer.12A preliminary study from a portion

of this

patient sample found no associations between prostate cancer and any food

recalled as

having been consumed during adolescence.20A U.S. study compared men newly

diagnosed with prostate cancer and healthy population-based controls in Georgia,

New

Jersey, and Michigan. Dairy product consumption was associated with prostate

cancer risk

among whites, but not blacks.13

These studies have the methodologic strengths of statistical adjustment for age

and other

factors and reasonably large sample sizes (Table 1). Of those studies finding

positive but

nonsignificant associations between dairy use and prostate cancer, several used

smaller

sample sizes or failed to adjust for age or other variables (Table 1). In Los

Angeles and

Chicago, prostate cancer patients were matched to hospital controls, finding

nonsignificant

increases in dairy product consumption among cancer patients.14 A Minnesota

study

comparing prostate cancer patients with hospital and neighborhood controls

reported

nonsignificant increases in dairy product consumption among cancer patients.15

Similarly,

a small study in Japan comparing prostate cancer patients to healthy controls

from a

prostate cancer-screening program found a nonsignificant increased risk

associated with

daily milk consumption.16 In Athens, Greece, prostate cancer patients were

compared

with hospital controls. Milk and dairy product consumption was marginally

positively

associated with prostate cancer risk.17

A Swedish case-control study including men with prostate cancer and unrelated

controls

drawn from a twin registry found no relationship between cancer risk and any

dietary

factor.18 An English study compared prostate cancer patients to controls with

benign

prostatic hyperplasia (BPH) and hospital controls with non-urological disease;

data for

both groups of controls were combined. The study reported no association between

dairy

product consumption and prostate cancer risk. The use of BPH patients as

controls in this

study may have reduced its sensitivity, as BPH may have antecedents similar to

those of

prostate cancer.19

Cohort Studies

Five of 11 cohort studies have found significant associations between milk or

dairy

product consumption and prostate cancer incidence or mortality.21-25 Six studies

found

no association between milk or dairy product use generally and prostate cancer

incidence

or mortality.26-31

A 20-year study of prostate cancer mortality among California Seventh-day

Adventists

reported a dose-related increased risk of age-adjusted prostate cancer mortality

with

milk consumption (for >3 glasses daily, RR = 2.4, 95% CI, 1.3-4.3; for 1-2

glasses daily,

RR = 1.8, 95% CI, 1.0-3.0, compared to <1 glass per day.) In a multivariate

analysis

adjusting for age, education, body weight, and consumption of meat, milk,

cheese, and

eggs, the relative risk of fatal prostate cancer associated with drinking >3

glasses of milk

per day was reduced to 1.5 and was no longer statistically significant

(p<0.10).21

However, adjustment for cheese consumption may be inappropriate if the relevant

dietary

factor is dairy product consumption generally. Similarly, adjustment for body

weight may

be inappropriate if increased body weight is one of the mechanisms by which

dairy

product consumption influences prostate cancer risk. A separate study of

California

Adventists studied cancer incidence, rather than mortality, finding no

relationship with

milk consumption.27

A dose-response relationship was also suggested by a cohort study including

various

ethnicities in Hawaii. Relative risks of prostate cancer, adjusted for age,

ethnicity, and

income, for men in the middle and highest tertiles of milk consumption were 1.3

(CI, 1.0–

1.9) and 1.4 (CI, 1.0-2.1), respectively, compared with the lowest tertile.

Although these

95 percent confidence intervals included 1.0, a statistically significant trend

was reported

(Ptrend = 0.04).22

In the Health Professionals Follow-Up Study, a cohort of U.S. male dentists,

optometrists,

osteopaths, pharmacists, and veterinarians, relative risk of advanced prostate

cancer

associated with daily consumption of more than two glasses of milk, compared to

zero,

was 1.6 (95% CI, 1.2-2.1, Ptrend = 0.002). For metastatic disease, relative risk

was 1.8

(95% CI, 1.2-2.8, Ptrend = 0.01). Of the milk consumed, 83 percent was skim or

low-

fat.23

The Netherlands Cohort Study reported a trend of increased prostate cancer risk

with

increasing milk consumption after adjustment for age, family history of prostate

cancer,

and socioeconomic status, although the difference in risk, compared with the

lowest

(index) quintile of milk consumption, was significant only for the 4th quintile

(RR= 1.63,

95% CI, 1.20-2.20, Ptrend = 0.02).24

In the Physicians' Health Study cohort, consumption of two and one-half dairy

servings

daily was associated with increased risk of prostate cancer, compared with

having less

than one-half serving daily, after adjustment for age, smoking, exercise level,

and body

mass index (BMI).25

Among the studies finding no association between dairy product use and prostate

cancer,

one, conducted in Norway, found a significantly increased age-adjusted risk of

prostate

cancer with consumption of skim milk, compared with whole milk (incidence rate

ratio 2.2,

95% CI, 1.3-3.7), although milk consumption in general was not associated with

risk. The

authors speculate that the relatively young age of their sample (mean age 43

years, range

16-56 years, at the outset of a nine- to 15-year follow-up period) may have

reduced

study sensitivity.31

Hirayama found a protective effect of green and yellow vegetables, but no

detectable

effect of milk consumption. Although the cohort was large (112,261 men), it

identified

only 63 cancer deaths during the follow-up period, and did not limit the

inclusion of the

oldest participants. Milk consumption was probably uncommon in this group, but

the

number of men consuming milk with various frequencies was not reported.26 In a

cohort

of men of Japanese ancestry living in Hawaii, there was no association between

milk

consumption and age-adjusted prostate cancer risk. Milk consumption was

uncommon;

only 34 percent of cases consumed milk five times per week or more.28 In a

Rancho

Bernardo, Calif., cohort (aged 50-84 at the study's outset), no relationship was

found

between whole milk consumption and prostate cancer incidence during 14-year

follow-

up, after adjustment for age, history of heart disease or diabetes, BMI,

systolic blood

pressure, smoking, and plasma cholesterol concentration. Milk consumption

averaged 0.5

cups per day.29 In a cohort of white male policyholders of the Lutheran

Brotherhood

Insurance Society, most of whom lived in Minnesota and the northeastern U.S., no

associations were identified between prostate cancer mortality and any dietary

factor. The

authors cautioned that the lack of an association between dietary factors and

cancer risk

may be partially due to the limited number of items in the food-frequency

questionnaire

and the homogeneous nature of the cohort, heavily weighted toward individuals of

Scandinavian descent.30

In summary, six of 12 case-control studies and five of 11 cohort studies found

significant

associations between milk or dairy product consumption and prostate cancer

incidence

and mortality. Particularly among cohort studies, those reporting significant

associations

were generally larger and more recent.

Mechanisms

Dairy products may influence the incidence or progression of prostate cancer by

several

possible mechanisms. One for which evidence is particularly compelling is the

effect of

high-calcium foods on vitamin D metabolism. In several prospective studies,

calcium

intake has emerged as an independent predictor of prostate cancer risk.12,23,25

Vitamin

D is derived either by conversion from 7-dehydrocholesterol in a reaction

catalyzed by

ultraviolet light, or from dietary sources. For conversion to the biologically

active hormone,

a hydroxyl group is added in the liver to form 25(OH) vitamin D, and a second

hydroxyl

group is added in the kidney, producing 1,25(OH)2 vitamin D.

Vitamin D receptors are present on prostate epithelium. Among other functions,

1,25(OH)2 vitamin D reduces cell proliferation and enhances cell

differentiation.32 An oral

calcium load suppresses parathyroid hormone secretion which, in turn, reduces

renal

1,25(OH)2 vitamin D production. Calcium itself also downregulates this reaction.

Although

some dairy products are supplemented with vitamin D, this inactive prehormone

does not

appreciably increase 1,25(OH)2 vitamin D blood levels, and the net effect of

dairy

consumption is a reduction in blood levels of this active form of the hormone.

Milk's high

content phosphorus and animal protein may aggravate this effect.32

Dairy product consumption has also been shown to increase serum concentrations

of

insulin-like growth factor (IGF-I).33,34 In in-vitro studies, IGF-I has

mitogenic and

antiapoptotic properties on prostate epithelial cells.35,36 Case-control studies

in diverse

populations have shown a strong and consistent association between serum IGF-I

concentrations and prostate cancer risk.37 In men and women aged 55 to 85 years,

the

addition of three daily eight-ounce servings of nonfat or 1 percent milk for 12

weeks was

associated with a 10 percent increase in serum IGF-I concentration (P<0.001).34

Mean

serum IGF-I concentration among vegans was shown to be 8 percent lower than

among

ovolactovegetarians (P=0.01) and 9 percent lower than among meat-eaters

(P=0.01).38

Changing dietary protein sources from animal sources to plant sources has been

shown to

reduce serum IGF-I concentrations.39

Most dairy products contain substantial amounts of fat and are devoid of fiber,

a

combination that is likely to increase serum testosterone concentration and

activity, with a

mitogenic effect on prostate tissue.40 However, several studies have found an

association

of dairy product intake with prostate cancer incidence and mortality that is

independent of

total fat intake and other dietary variables.25,40,41

Dietary factors other than dairy products are also associated with risk.

Generally speaking,

diets high in animal products are associated with higher risk, while those rich

in plant

foods, particularly tomatoes, are associated with reduced risk.2 Daily soymilk

consumption was associated with a significant reduction in prostate cancer risk

in a

cohort of 13,855 Seventh-Day Adventist men (RR = 0.3, 95% CI, 0.1-1.0, compared

with

those never drinking soymilk).42 Isoflavones in soymilk inhibit growth of human

prostate

cancer cells and also inhibit 5a-reductase, an enzyme that converts testosterone

to 5a-

dihydrotestosterone in the prostate.42 A similar beneficial effect was

demonstrated for

tofu consumption.28 Based on experience with a case-control study in Athens,

Greece,

researchers calculated that the combined effect of reducing dairy consumption,

substituting olive oil for other added fats, and increasing tomato intake to the

levels

consumed by those in the lowest risk categories could reduce prostate cancer

risk in their

population by 41 percent (95% CI, 23-59%).43

Conclusions

Evidence from international, case-control, and cohort studies suggests that men

who

avoid dairy products are at lower risk for prostate cancer incidence and

mortality,

compared with others. In case-control and cohort studies, the relative risk of

prostate

cancer among subgroups with the most frequent milk consumption, compared with

those

at the lowest consumption levels, falls in the range of 1.3 to 2.5. These

findings raise two

important questions: Does the observed relationship represent cause and effect,

and is

available evidence sufficient to justify a recommendation that milk-drinking men

alter

their dietary habits?

Findings supporting a cause-and-effect relationship include the relative

consistency of

this association in diverse populations, evidence of a dose-response

relationship,

plausible biological mechanisms that underlie the observed associations, and no

reasonable alternative explanation for these findings. Perspective is lent to

the second

question by a comparison with evidence linking alcohol use and breast cancer

risk.

Although somewhat fewer studies have addressed the association between milk and

prostate cancer, their demonstrated effect, strength, and consistency of

evidence

approach those relating alcohol to breast cancer risk, an association that is

now widely

accepted and incorporated into the Dietary Guidelines for Americans.44 A pooled

analysis

of cohort studies showed that the adjusted relative risk of incident breast

cancer for

women consuming two to five drinks (30-60 grams of alcohol) per day was 1.41

(95% CI,

1.18-1.69).45 In a 1997 review by the World Cancer Research Fund and the

American

Institute for Cancer Research, six of 11 cohort studies and 15 of 36

case-control studies

found such an association.46

Men who choose to avoid dairy products reap other nutritional benefits, such as

a

reduction in total fat, saturated fat, and cholesterol intake. Unless they

replace dairy

products with calcium-fortified products or calcium supplements, they are likely

to reduce

their calcium intake in the process. However, a reduction in calcium intake may

be an

important mechanism by which reducing or avoiding dairy products reduces

prostate

cancer risk. Moreover, there is no apparent risk to moderate reductions in

calcium intake.

There is little evidence to suggest that a high intake of calcium from dairy or

other sources

reduces the risk of osteoporotic fractures among men. Few studies have examined

the

effect of dietary calcium on osteoporosis risk in adult men independently of

vitamin D

intake.47 There has been some indication that a higher intake of calcium,

including that

from dairy sources, in the context of an omnivorous American diet, is associated

with

reduced recurrence of colonic adenomatous polyps.48 However, in Africa, in the

context

of a low-calcium, low-dairy diet, both adenomatous polyps and colon cancer are

much

rarer than in Western countries.49 Some studies suggest that calcium, including

that in

dairy products, may reduce blood pressure, but the effect, if any, is small (on

the order of

<2 mm Hg systolic and <1 mm Hg diastolic), far smaller than the effect of adding

vegetables and fruits to the diet.50-51

In conclusion, several lines of evidence indicate that consumption of dairy

products is

associated with increased risk of prostate cancer incidence and mortality.

Avoidance of

these products may offer a means of reducing risk of this common illness.

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Table 1. Case-Control Studies of Dairy Product Intake and Prostate Cancer

Author, Year, Location

No. of Cases

Findings Related to Dairy Intake RR (95% CI), where applicable

Ajustment

Age

Location

Weight

Other

Rotkin, 1977, USA

111

Cases consumed more dairy (ns)

n

n

n

n

Schuman et al., 1982, USA

240

Cases consumed more dairy (ns)

n

n

n

n

Mishima et al., 1985, Japan

100

Cases consumed more dairy (ns)

n

n

n

n

Talamini et al., 1986, Italy

166

milk/dairy>5/wk vs less often

2.5 (1.3-4.7)

y

n

y

y

Mettlin et al., 1989, USA

371

milk 3 servings/d vs none

2.49 (1.27-4.87)

y

y

n

n

Talamini et al., 1992, Italy

271

milk>10/wk vs <2/wk

1.58 (1.06-2.36)

y

y

y

y

De Stefani et al., 1995, Uruguay

156

milk>2 servings/d vs <1/d

1.7 (1.1-2.9)

y

y

n

n

et al., 1996, USA

483 white

449 black

milk: h vs 1 quartile

1.7 P=0.03

milk: h vs 1 quartile

0.9 P=0.75

y

y

n

n

n

n

n

n

Grönberg et al., 1996, Sweden

406

milk: >5 servings/d vs 0 servings/d

0.84 (0.44-1.57)

Ptrend=ns

y

n

n

n

Ewings et al., 1996, UK

159

>7 pints/wk (ns) vs <3 pints/wk

0.95 (0.50-1.83)

y

n

n

n

Chan et al., 1998b, Sweden

526

dairy>4.5 servings/d vs <2.5 servings/d

1.49 (1.01-2.19)

y

n

y

n

Tzonou et al., 1999, Greece

320

quintile trend

1.6 P=0.12

y

n

y

y

Table 2. Cohort Studies of Dairy Product Intake and Prostate Cancer

Author, Year, Location

Size of Cohort Cases/

Death

Findings Related to Dairy Intake RR (95% CI), where applicable

Ajustment

Age

Location

Weight

Other

Hirayama, 1979, Japan

112,261

63 deaths

milk daily vs rarely or never (ns)

n

n

n

n

Snowdon et al., 1984, USA

6,763

99 deaths

milk>3 servings/d vs <1/d

2.4 (1.3-4.3)

(multivariate: 1.5, P<0.10)

y

y

n

n

n

y

n

y

Mills et al., 1989, USA

14,000

180 cases

milk>daily vs never

0.80 (0.54-1.19)

y

n

n

n

et al., 1989, USA

1,776

100 cases

per cup/d

1.0 (0.9-1.2)

y

n

y

y

Severson et al., 1989, USA

7,999

174 cases

milk>5 servings/wk vs <1 serving/wk

1.00 (0.73-1.38)

y

n

n

n

Hsing et al., 1990, USA

17,633

149 deaths

dairy>86 servings/mo vs <26 servings/mo

1.0 (0.6-1.7)

y

n

n

y

LeMarchand et al., 1994, USA (Hawaii)

20,316

198 cases

milk, high vs low tertile

1.4 (1.0-2.1)

y

n

n

y

Veierød et al., 1997, Norway

25,708

72 cases

milk, not quantified (na)

y

n

n

n

Giovannucci et al., 1998a, USA

47,781

1,369 cases

milk>2 servings/d vs none

1.6 (1.2-2.1)

y

n

y

y

Schuurman et al., 1999, Netherlands

58,270

642 cases

milk, high vs low quintile

1.12 (0.81-1.56) Ptrend=0.02

y

n

n

n

Chan et al, 2000, USA

20,885

1,012 cases

dairy>2.5 servings/d vs <0.5 serving/d

1.34 (1.04-1.71)

y

n

y

y