Health Effects of Cows’ Milk
http://www.eps1.comlink.ne.jp/~mayus/eng/index.html

Milk from Pregnant Cows Is Responsible for theDevelopment of Breast, Ovarian and Corpus Uteri Cancers
Adapted from
Ganmaa D and Sato A.
The Possible Role of Female Sex Hormones in Milk from Pregnant Cows in theDevelopment of Breast, Ovarian and Corpus Uteri Cancers.
Medical Hypotheses 2005; 65 (6): 1028-37.

Abstract
The continued increase in incidence of some hormone-related cancers worldwide is of great
concern. Although estrogen-like substances in the environment were blamed for this increase, thepossible role of endogenous estrogens from food has not been widely discussed. We areparticularly concerned about cows’ milk, which contains a considerable quantity of estrogens.
When we name cows’ milk as one of the important routes of human exposure to estrogens, thegeneral response of Western people is that “man has been drinking cows’ milk for around 2,000
years without apparent harm.” However, the milk that we are now consuming is quite different
from that consumed 100 years ago. Unlike their pasture-fed counterparts of 100 years ago,modern dairy cows are usually pregnant and continue to lactate during the latter half ofpregnancy, when the concentration of estrogens in blood, and hence in milk, increases.
The correlation of incidence and mortality rates with environmental variables inworldwide countries provides useful clues to the etiology of cancer. In this study, we correlated
incidence rates for breast, ovarian, and corpus uteri cancers (1993-97 from Cancer Incidence inFive Continents) with food intake (1961-97 from FAOSTAT) in 40 countries. Meat was mostclosely correlated with the breast cancer incidence (r=0.827), followed by milk (0.817) andcheese (0.751). Stepwise multiple-regression analysis (SMRA) identified meat as the factor
contributing most greatly to the incidence of breast cancer ([R]=0.862). Milk was most closely
correlated with the incidence of ovarian cancer (r=0.779), followed by animal fats (0.717) andcheese (0.697). SMRA revealed that milk plus cheese make the greatest contribution to theincidence of ovarian cancer ([R]=0.767). Milk was most closely correlated with corpus uteri
cancer (r=0.814), followed by cheese (0.787). SMRA revealed that milk plus cheese make themost significant contribution to the incidence of corpus uteri cancer ([R]=0.861). In conclusion,increased consumption of animal-derived food may have adverse effects on the development of1

hormone-dependent cancers. Among dietary risk factors, we are most concerned with milk anddairy products, because the milk we drink today is produced from pregnant cows, in which
estrogen and progesterone levels are markedly elevated.

Introduction
Breast cancer is one of the most frequent cancers among women (1). The incidence of breast
cancer has been increasing in both developed and developing countries (2). The fact that people
from low-risk countries increase their risk on immigrating to higher-risk countries suggest thatsome modifiable lifestyle and/or environmental factors are responsible for the development ofbreast cancer (3). It has been postulated that most cancer-afflicted women develop subclinicalbreast cancer at an early age and that diet plays an important role in the progression from suchlesions to clinical disease (4). In addition, the variation in the breast cancer incidence rateworldwide suggests that lifestyle factors, especially diet, influence breast cancer risk.
Epithelial ovarian cancer kills more women each year than all other gynecological cancers
combined (5). The incidence of ovarian cancer also varies widely among countries. In general,
incidence rates are higher in developed than in less developed countries. Rates are higher among
younger Chinese and Japanese women born in the United States than among their Asian-born
counterparts (6). Such immigration studies suggest that lifestyle and environmental factors play amajor role in the etiology of this malignancy.
Endometrial cancer is the sixth most common cancer worldwide, accounting for ~2% of
all cancers in women (7). As with breast and ovarian cancers, there is a wide difference in theincidence rate of corpus uteri cancer across countries. The rate amongst U.S. Japanese is severalfold higher than that for Japanese living in their native country (3). This finding suggests thatlifestyle and environmental factors, rather than hereditary influence, affect the incidence of thiscancer.
The common feature of breast, ovarian, and corpus uteri cancers is that they arecomparatively rare in women under 40 years of age. The risk increases sharply after around age
40 and peaks between the ages of 65 and 79 (8). The three malignancies share common risk
factors, including obesity, menarche at young age, late menopause, and nulliparity, in addition to
an increased risk inherent to and dependent upon family history (5). In addition, the risk of thesethree cancers changes within a few years of shifts in exposure to sex hormones, and some of thechanges in risk persist for many years, indicating that hormones can affect both early and latestages of carcinogenesis. Sex hormones may play a major role in their etiology, likely bycontrolling the rate of cell division, cell differentiation, and number of susceptible cells (9).
According to Armstrong and Doll (10), the correlation of incidence and mortality ratewith the prevalence of environmental agents in various geographical areas provides useful clues2

to the etiology of cancer. In this study, we used incidence and mortality data for the three mostprevalent female cancers –breast, ovarian, and corpus uteri cancers from 40 countries– andcorrelated the rates with dietary variables.

Materials and Methods
Cancer incidence
Cancer Incidence in Five Continents edited by Parkin et al. (11) provided us withcomparable data on the incidence of cancer between 1993 and 1997 in different geographicallocations (200 populations in 50 countries). In this study, we used data from 40 of these countries,
for which both cancer incidence rates and food consumption data from FAOSTAT Database
Collections (12) were available. The age-specific incidence rates were standardized to the world
population and the mean value of the age-adjusted incidence rates were calculated.
Several countries have more than one cancer registry. If more than one registry wasavailable for a country, those that stated “The editors were unable to verify these data” were
excluded from this study. The remaining age-specific incidence rates in the same country werestandardized to the world population. The mean age-adjusted incidence rate was used as arepresentative rate for Australia, Brazil, China, France, Germany, India, Italy, Japan, Poland,
Spain, Switzerland, Thailand, and the United Kingdom.
In some countries, cancer registries provided data for different ethnic groups. In this study,
the rates for Africans were used for Zimbabwe; those for all Jews were used for Israel; those for
Kuwaitis were used for Kuwait; and those for non-Maori were used for New Zealand.
In several countries, only one cancer registry reported data to the IARC. The incidence
rate from the registry was then assumed to represent the incidence for the whole country (Algeria,
Argentina, Austria, Columbia, Costa Rica, Ecuador, Ireland, Korea, Mali, Malta, Philippines,
Uganda, Uruguay, and Viet Nam).
Canada, Denmark, Finland, Hong Kong, Iceland, The Netherlands, Norway, and Swedencollected data for their cancer registries on a national basis. The incidence rates for thesecountries were used as provided.
Many cancer registries operate in the United States. Of these, the registry for Caucasians
produced by the Surveillance, Epidemiology, and End Results (SEER) program was used as
representative for the United States.
The age-specific mortality rates of cancers that are listed in GLOBOCAN 2000 (13) wereused in this study. The countries selected were the same as those used for the incidence.
Food consumption
The consumption data (Mt/1000 capita/year) for various food items from 1961 to 19973

available from the FAOSTAT Database Collections (12) were used. The food items used for thisstudy were animal fats, meat (beef, pork, poultry, mutton, and goat meat), eggs, butter, milk
(excluding butter), whole milk, cereals (excluding wine), pulses, beans, soy beans, peas, fruits(excluding wine), vegetables, coffee, tea, and alcoholic beverages. The consumption of each foodor drink was converted from Mt/1000 capita/year to g/capita/day.
Statistical analysis
All of the data were analyzed by a statistical software (SAS Institute, Cary, NC). The 0.05
level of probability was used as the criterion for significance. Simple correlation coefficients (r)were calculated to examine the association between the incidence or mortality rates of breast,
ovarian, and corpus uteri cancers and the consumption of each food item. Consumption of several
food items was closely interrelated (collinearity, r > 0.8). For example, the r value calculated forthe correlation between the amount of milk and cheese consumed in 1961-97 was 0.812. Hence,
consumption of milk and cheese in the same period was grouped as “milk + cheese.” Thecontributions of these grouped food items to incidence or mortality were evaluated by stepwise
multiple-regression analyses. The following eleven food items were selected for the analysis(independent variables): “animal fats + butter,” “milk + cheese,” eggs, meat, cereals, pulses,
fruits, vegetables, vegetable oils, coffee, and alcohol.

Results
Incidence of breast cancer and food intake
The age-adjusted incidence
rates per 100,000 for breast cancer
differed markedly from one country toanother. For example, Uruguay had thehighest rate at 114.9, followed by theUnited States (92.1) and Israel (87.1)(Figs. 1 and 2). The lowest rate wasfor Korea (12.7), followed by Thailand(16.1) and Mali (20.0).

Fig. 1. Correlation between the age-adjusted incidence of breast cancer and per capita meat
consumption.

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The simple correlation
coefficients between the incidence rateof breast cancer and food intake in 40
countries are shown in Table 1. Of thefood items examined, meat was themost closely correlated with incidenceof this cancer incidence (r=0.827)(Fig.1), followed by milk (0.817) (Fig.
2) and cheese (0.751). By contrast,
cereals (-0.467) and pulses (-0.438)
were negatively correlated with theincidence of breast cancer.
Stepwise multiple-regression
analysis revealed that meat (1961-97)
contributed most to the incidence ofbreast cancer in 1993-97 (standardized
regression coefficient [R]=0.862)(Table 2)

Fig. 2. Correlation between the age-adjusted incidence of breast cancer and per capita milk
consumption.
The correlation coefficient between the age-adjusted incidence rate and age-adjusted
mortality rate of breast cancer in the 40 countries examined was r=0.872. The age-adjusted
mortality rates of breast cancer had the highest correlation with cheese consumption (r=0.725),
followed by fats (0.670) and butter (0.595) (Table 3).

5Incidence of ovarian cancer and food intake
Iceland had the highest ovarian cancer incidence at 16.2 per 100,000, followed by Sweden(15.2) and the United Kingdom (13.7) (Fig. 3). The lowest rate per 100,000 was for Korea (1.6),
followed by Mali (2.1), China (4.0), and Brazil (4.0)
The simple correlation coefficient, r, showed the greatest correlation between milk andovarian cancer (r=0.779), followed by animal fats (0.717) and cheese (0.697) (Table 1). By
contrast, cereals (r=-0.520) and pulses (-0.465) were negatively correlated with the incidence ofovarian cancer.
The results of stepwise multiple-regression analysis are presented in Table 2. The analysis
identified “milk + cheese” as the factor contributing most to the incidence of ovarian cancer(standardized regression coefficient [R]=0.767), while it identified cereals as a factor contributing
to a decreased incidence.

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The correlation coefficient
between mortality and incidence ofovarian cancer was as high as r=0.808.
The food most closely correlated withmortality due to ovarian cancer wasfats (r=0.818), followed by milk
(0.790) and cheese (0.731). Cereals, bycontrast, were negatively correlatedwith the mortality (-0.391) (Table 3).

Fig. 3. Correlation between the age-adjusted incidence of ovarian cancer and per capita
milk consumption.

Incidence corpus uteri cancer and food intake
The age-adjusted incidence rate (per 100,000) of corpus uteri cancer was highest in the
United States (18.4), followed by Malta (16.3) and Canada (14.4). Viet Nam had the lowest
incidence rate at 1.6, followed by Mali (1.7) and Korea (1.9) (Fig. 4).
Milk was most closely correlated with the incidence of corpus uteri cancer (r=0.814),
followed by cheese (0.787) and meat (0.782) (Table 1). Conversely, pulses were negatively
correlated with the incidence of this cancer (-0.437).
Stepwise multiple-regression-analysis identified “milk + cheese” as the factor
contributing most to an increased incidence of corpus uteri cancer (standardized regression

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coefficient [R]=0.861) (Table 2).
The mortality rates of corpus
uteri cancer were weakly correlatedwith its incidence rate (r=0.251). The
highest age-adjusted mortality rate was
4.4 for Uruguay, and Mali had thelowest rate of 0.24. As with theincidence data, the age-adjusted
mortality rates of this cancer had thehighest correlation with milk
consumption (r=0.545), followed bycheese (0.406) and animal fats (0.403).
Fig. 4. Correlation between the age-adjusted incidence of corpus uteri cancer and per capita
milk consumption

Discussion
Epidemiological studies that correlate cancer incidence and mortality rates with the dietary
practices in various geographical areas have certain shortcomings. The rates of incidence andmortality of any cancer are affected by regional differences in diagnosis, registration andcertification, and the fatality rate of the cancer. The cancer incidence and mortality data fromdeveloping countries are clearly less complete than those from developed countries because ofproblems with underdiagnosis and undercertification due to the local medical and economic
background, together with problems enumerating the population. In addition, the consumption
data for each food item in a country are not based on actual nutrition surveys, but are roughly
estimated using the following equation: food supply per capita = (production + import + stockchanges - export - feed - seed - processing - waste - other uses)/population. Hence, it is difficult
to determine the extent to which the available food data translates into daily per capita
consumption. Nevertheless, the overall relationships are convincing, plausible, and at least serve
as guides for further epidemiological and experimental studies (10,14).
Breast cancer
Early diagnosis (mammography, fine-needle biopsy), treatment (lumpectomy,
radiotherapy, chemotherapy) and increasing public awareness of breast cancer may havecontributed to its relatively stable mortality rates despite its increasing incidence. Starting in the81990s, breast cancer mortality began to decline in the United States and in some European
countries (8). Since the 1950s, however, both incidence and mortality rates have been increasing
in a number of other countries, including low-risk countries such as China (15) and Japan (16).
Lifestyle changes in these countries, such as diet, likely account for much of this increase.
In this study, the food that was most closely correlated with the incidence of breast cancer
was meat, followed by milk and cheese. Many other epidemiological studies have found positive
correlations between breast cancer risk and the consumption of meat, milk, and dairy products(14,17-21). According to La Vecchia and Pampallona (18), who found a significantly positive
correlation between breast cancer mortality and meat and milk consumption, milk and cheese
were the only dietary variables to remain significantly positive after the correlation was adjusted
for the women’s age at the birth of their first child and economic variables.
Since dietary fat has long been considered a major risk factor for breast cancer, special
attention has been given to the high fat content of milk (17,19,21-23). However, milk fat cannot
account for all of the breast cancer risk related to milk consumption. In fact, consumption ofwhole milk has declined steadily since the 1950s, and been replaced by fat-reduced milk (24), yet
the incidence of breast cancer has increased worldwide over the last 50 years (25).
Estrogens and progesterone are breast cancer promoters because of their physiologicalroles stimulating the mammary gland (26). The major sources of animal-derived estrogens in thehuman diet are milk and dairy products, which account for 60-80% of the estrogens consumed(27). Most milk for human consumption is obtained from heifers in the latter half of pregnancy,
when the estrogen levels in cows are markedly elevated (28).
Although the oral bioactivity of free estradiol and estrone may be relatively low, estrone
sulfate, which is a major estrogen in milk, has high oral bioactivity. Once inside the body it canbe readily converted to estrone and estradiol. Postmenopausally, estrone is the source of mostcirculating estradiol, and estrone sulfate is the most abundant circulating estrogen (29). In
addition to the long plasma half-life of estrone sulfate, it is absorbed in the intestinal mucosa
either virtually unchanged (30,31) or by enterohepatic circulation. Remesar et al. (32) calculated
estrone intake in a standard human diet and found that 46.6% of estrone came from dairy
products.
Recently, we confirmed that commercially available low-fat milk promotes thedevelopment of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats (33).
In order to specify the role of estrogens on the development of mammary tumors, an aqueous
estrone sulfate solution was used as a positive control in this study. The degree of tumor
promotion by cows’ milk was almost comparable to that of 100 ng estrone sulfate per milliliter.
Some human studies have also demonstrated that milk consumption increases thecirculating estrogen level. South African black males who had switched from a vegetarian diet to9a Western diet with milk, butter, and meat showed an increase in circulating estrogen levels (34).
The relationship between milk consumption and plasma estrogen concentrations is also supportedby the fact that Asian women, whose consumption of milk and dairy products is low, have lower
plasma estrogen concentrations than those of Caucasian women, whose dairy productconsumption is high (35).
In addition to estrogens, milk also contains insulin-like growth factor I (IGF-I) in
nanomolar concentrations (36). IGF-I plays a role in the growth and incidence of neoplastic
pathology (37) by regulating the growth of cancer cells and it stimulates the proliferation ofhuman breast cancer cell line MCF-7 (38). Further, estrogen and IGF-I have mutually favorable
actions on breast cancer cell proliferation. In a human study, plasma IGF-I concentration
increased by 10% when healthy subjects consumed cows’ milk (39). In fact, the consumption ofcommercial milk pasteurized by heat at 125-130 ºC was confirmed to increase the plasma level of
IGF-1 in rats (33).
Obesity has been linked with breast, corpus uteri and ovarian cancers, probably via its
effect on circulating estrogens (40,41). This finding is biologically plausible, since a greater
amount of fat results in greater conversion of androstenedione to estrone by aromatase and lower
levels of sex hormone-binding-globulin (SHBG), which leads to higher levels of bioavailable
estrone and estradiol (42). We should pay particular attention to the sex hormone in modern
cows’ milk, because epidemiological studies of large scale have repeatedly confirmed theincreased incidence of breast cancer in postmenopausal women who are currently undergoinghormone replacement therapy (43,44).
Ovarian cancer
The strong correlation between ovarian cancer and per capita milk consumption led to the
hypothesis that consumption of lactose is a risk factor for ovarian cancer (8). In the Iowa
Women’s Health Study, a prospective study of 41,836 women, high lactose consumption was
associated with an increased risk of ovarian cancer (r=1.60) (45). Cramer (46) proposed thatgalactose, a component sugar of lactose, is a risk factor for ovarian cancer, as galactose is toxic tooocytes. Hypogonadism or ovarian failure in response to gonadotropin stimulation has beenfound in women who are deficient in the enzyme galactose-1-phosphate uridyltransferase(GALT) (47). In one case-control study, GALT activity was significantly lower in cases ofovarian cancer (48). Nevertheless, most case-control studies that have examined the risk ofovarian cancer in relation to lactose intake have not reported a substantial association between thetwo (49,50). A recent prospective cohort study in Sweden (51) indicated that high intakes oflactose and dairy products, particularly milk, are associated with an increased risk of serious
ovarian cancer but not of other subtypes of ovarian cancer.
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Several research groups have reported associations between ovarian cancer and the intakeof specific milk products, such as butter (52,53), whole milk (53-55), skim milk (45), yogurt (4855), cottage cheese (48), and ice cream (53). One study found a three-fold greater risk of ovariancancer among women who drank at least one glass of whole milk per day compared with those
who did not (54). Risk was also elevated for non-fat milk, eggs and cheese, and dairy products ingeneral (45).
In our study, the stepwise multiple-regression analysis revealed that “milk + cheese”
contributed the most to the incidence of ovarian cancer. Our results are consistent with previous
ecological studies that found an association between ovarian cancer and milk consumption (14).
The etiology of ovarian cancer is still poorly understood, although it is clear that hormonal
factors are involved. Higher IGF-I levels and reduced IGF-I binding protein levels have also beenfound in patients suffering from ovarian cancer (56,57). Epidemiological observations andexperimental data indicate that estrogens have an adverse effect on the ovarian epithelium (7). It
is not unreasonable to presume that estrogens and growth factors in milk and dairy products areassociated with the development of ovarian cancer by changing the hormonal environment in theovaries.
Corpus uteri cancer
Cancer of the corpus uteri is a typical model of hormone-related carcinogenesis. Indeed,
the effect of estrogens is so direct and strong that the widespread use of hormone therapy
increased the incidence of this cancer in the United States to almost epidemic proportions (8).
Most of the risk factors for corpus uteri cancer can be explained within the framework of theunopposed estrogen hypothesis, which holds that exposure to estrogens leads to increased mitotic
activity of endometrial cells, an increased number of DNA replication errors, and somatic
mutations resulting in a malignant phenotype (58,59).
In our study, the incidence of corpus uteri cancer was most closely correlated with theconsumption of milk and cheese. As discussed in the section on breast cancer, milk and dairy
products contain considerable amounts of estrogens and growth factors. Estrogens induce various
tumors in laboratory animals and have been recognized as carcinogens in humans, raising the risk
for uterine cancer, in addition to breast and ovarian cancers (60). Several trials have established alink between endometrium cancer and the IGF system (61-63), including the stimulating effect of
IGF-I in vitro on endometrial cancer cells, and increased circulating levels of serum IGF-I and
decreased insulin-like growth-factor-binding protein (IGFBP-1) in women with corpus uteri
cancer.
In conclusion, we hypothesize that female sex hormones in milk and dairy products havea common effect on the development of breast, ovarian and corpus uteri cancers. Further
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epidemiological and mechanistic studies are needed to verify this hypothesis.

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