|
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 twelve case-control studies,
six found significant associations, as did five of eleven 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 to those 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 to 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
to 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, NY, found
an increased risk of prostate cancer with the daily consumption
of three or more glasses of whole milk, compared to never drinking
milk.9In Montevideo, Uruguay, a comparison
of prostate cancer patients to 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
to having less than one serving per day.11 In Örebro county, Sweden,
men with prostate cancer were compared to 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.16In
Athens, Greece, prostate cancer patients were compared to 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 eleven 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, 1.01.9)
and 1.4 (CI, 1.0-2.1), respectively, compared to the lowest tertile.
Although these 95% 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%
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 to 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 to 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 to 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 9- to15-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% of cases consumed milk five times per week or more.28
In a Rancho Bernardo, California, 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 twelve case-control studies and five of eleven
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 3 daily eight-ounce
servings of nonfat or 1% milk for 12 weeks was associated with a
10% 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 to 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 to others. In case-control
and cohort studies, the relative risk of prostate cancer among subgroups
with the most frequent milk consumption, compared to 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 2-5 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 eleven cohort studies and fifteen of
thirty-six 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 |
Hayes 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 |
Thompson 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 |
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