International Dairy Journal 22 (2012) 3e14

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International Dairy Journal

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Review Impact of cows’ milk on cancer risk

Peter W. Parodi*

Human Nutrition and Health Research, Dairy Australia, Melbourne, Australia article info abstract

Article history: have been implicated in cancer at hormone-responsive sites, such as the , ovaries, Received 20 May 2011 endometrium and prostate. Because cows’ milk contains estrogens, some authors have suggested that its Received in revised form consumption may contribute to the risk of cancer at these sites. However, these reports do not recognize 12 August 2011 the complex mechanisms these cells possess to regulate levels. Hormone-responsive and many Accepted 14 August 2011 peripheral cells contain all the necessary steroidogenic necessary for in situ synthesis of bioactive estradiol from abundant androgenic precursors and for inactivation of unwanted estrogens. Estradiol from dairy products is extensively inactivated in the gastrointestinal tract and only about 5% survives the first pass to the liver. Thus daily dairy product intake would supply only about 0.25% of the FAO/WHO upper acceptable daily intake of estradiol. Available epidemiological evidence does not suggest an association between dairy product consumption and risk of cancer of the breast, ovaries and endometrium. Ó 2011 Elsevier Ltd. All rights reserved.

Contents

1. Introduction ...... 4 2. Estrogens and cancer risk ...... 4 2.1. Observational studies ...... 4 2.2. Experimental studies and mechanisms ...... 4 3. Serum estrogen levels and the risk of cancer ...... 5 3.1. ...... 5 3.2. Endometrial cancer ...... 5 3.3. Ovarian cancer ...... 5 3.4. Prostate cancer ...... 5 4. Relationship between circulating estrogen levels and levels in breast tissue ...... 5 5. Relationship between urinary estrogens and estrogen metabolites in breast tissue ...... 6 6. Formation and transformation of tissue estrogen levels in the breast and other estrogen-responsive tissues ...... 6 7. Breast tissue estrogen content: uptake from the circulation versus synthesis in situ ...... 7 8. Estrogen content of cows’ milk ...... 8 8.1. Factors influencing the hormone content of milk ...... 8 9. Absorption and metabolism of estrogens from milk and its products ...... 9 10. Physiological influence of various exogenous sources of estrogen ...... 9 11. Epidemiological evidence ...... 11 11.1. Breast cancer ...... 11 11.2. Ovarian cancer ...... 11 11.3. Endometrial cancer ...... 11 11.4. Prostate cancer ...... 11 11.5. Colon cancer ...... 11 12. Conclusions ...... 12 References...... 12

* Tel.: þ617 3359 6110. E-mail address: [email protected].

0958-6946/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.idairyj.2011.08.006 4 P.W. Parodi / International Dairy Journal 22 (2012) 3e14

1. Introduction 2.2. Experimental studies and mechanisms

It is generally accepted that estrogens are involved in the There is ample evidence that administration of estradiol (17b- development of cancer at hormone-responsive sites, such as the estradiol) to laboratory animals induces tumors and that castration breast, ovary and endometrium and, in conjunction with testos- and use of drugs inhibits tumor development terone, the prostate (Bernstein & Ross, 1993; Kaaks, Lukanova, & (Bernstein & Ross, 1993; Liehr, 2000). The mechanisms whereby Kurzer, 2002; Lukanova & Kaaks, 2005; Risbridger, Bianco, Ellem, estrogens cause cancer have not been established conclusively. & McPherson, 2003). Even so, the mechanisms whereby estrogens A commonly held hypothesis is that circulating estrogens diffuse influence carcinogenesis remain largely unresolved. A number of passively through cellular membranes of estrogen-responsive cells publications have hypothesized that estrogen present in cows’ milk and bind to nuclear estrogen receptors (ERs) of which there are two may be responsible for the development of cancer in estrogen- forms, ERa and ERb. Binding to ERs stimulates transcription of responsive organs (Farlow, Xu, & Veenstra, 2009; Ganmaa & Sato, genes involved in proliferation. Rapidly proliferating cells are 2005; Outwater, Nicholson, & Barnard, 1997; Qin, Wang, Kaneko, susceptible to genetic errors during DNA replication, which if Hoshi, & Sato, 2004). However, these hypotheses fail to take into uncorrected may ultimately lead to cancer. Estradiol may also account the complex mechanisms involved in the synthesis and increase proliferation in cells already having mutations due to other metabolism of estrogens within the cell and the metabolic sources of DNA damage (Santen, 2002; Yager & Davidson, 2006; processes associated with the absorption of exogenous estrogens. Yue et al., 2003). These aspects, together with a brief outline of relevant aspects of It has also been proposed that non-receptor-mediated mutagen- estrogen carcinogenesis, are discussed in this review. esis induced by oxidized estrogen metabolites may contribute to carcinogenesis (Cavalieri, Devanesan, Bosland, Badawi, & Rogan, 2002a; Cavalieri et al., 2002b; Rogan et al., 2003; Yager & Davidson, 2. Estrogens and cancer risk 2006). Estrogen metabolites are formed by a series of oxidative biotransformations, both in the liver and in extrahepatic hormone- 2.1. Observational studies responsive organs by the activities of a series of cytochrome P450 enzymes. There are two major mutually exclusive pathways for The study of breast cancer has received more attention than the transformation of estradiol and . In the first pathway cancer at the other hormone-responsive sites. Nevertheless, the the A ring is hydroxylated at position 2 or 4 to produce the causes of breast cancer are still largely undetermined. Evidence catechol estrogens 2-hydroxyestradiol and 2-hydroxyestrone or 4- from a number of observational studies suggests that several hydroxyestradiol and 4-hydroxyestrone, respectively. These four reproductive factors, which indicate an increased exposure to metabolites may be inactivated in the liver and extrahepatic estrogens, increase breast cancer risk. Early menarche, late meno- estrogen-responsive tissue by glucuronidation and sulfation and pause, nulliparity and first pregnancy late in life are associated with particularly in extrahepatic tissues by the catechol-O- increased risk. Bilateral oophorectomy, especially at an early age, methyltransferase (COMT), which forms 2- and 4-methoxyestradiols, reduces risk. On the other hand, oral contraceptive use that and methoxyestrones. In certain conditions catechol estrogens may prevents and decreases serum estrogen levels results in be oxidized further to reactive semiquinones then a slight increase in risk. In contrast, breast-feeding (particularly for to catechol estrogen-2,3-quinones and catechol estrogen-3,4- long durations, which also prevents ovulation) is associated with quinones. Protection against the catechol estrogen-quinones occurs lower risk, but this protection may result from cell differentiation through conjugation with catalyzed by glutathione-S- (Bernstein & Ross, 1993; Chodosh et al., 1999; Harris, Lippman, transferases. Another protection mechanism results when catechol Veronesi, & Willett, 1992; Kuller, 1995). estrogen-quinones are re-cycled to catechol estrogens by the action of Evidence for a role of estrogens in endometrial cancer is robust quinone reductases (Cavalieri, Frenkel, Liehr, Rogan, & Roy, 2000; and it is considered that exposure to estrogens, unopposed by Lakhani, Sarkar, Venitz, & Figg, 2003; Yager & Davidson, 2006). The , is a major etiological factor. Early menarche and late second major oxidation pathway occurs at the D ring with the menopause are risk factors, whereas parity is protective. A low level formation of 16a-hydroxyestradiol and 16a-hydroxyestrone. These of physical activity and obesity increase risk, possibly due to 16a-hydroxyderivatives may be further oxidized to (Clemons & a reduction in progesterone levels. There is an increased risk of Goss, 2001; Mueck, Seeger, & Lippert, 2002). endometrial cancer in users of estrogen-only oral contraceptives Estrogenic and genotoxic properties of the various estrogen and hormone replacement therapy, but no increased risk when metabolites vary from one and other and from their parent estro- progesterone is included in the preparation (Kaaks et al., 2002; gens. For instance, the 2-hydroxyestrogens bind to ERs with affinity Pike, Spicer, Dahmoush, & Press, 1993). comparable with that for estradiol, but have limited mitogenic The cause of ovarian cancer is largely unknown. Observational effect and are considered antiestrogenic and anticarcinogenic evidence on the role of estrogens is conflicting and often open to (Bradlow, Telang, Sepkovic, & Osborne, 1996; Mueck et al., 2002). 2- alternative interpretation. There is some support for the concept Methoxyestradiol has very low affinity for ERs, but exhibits potent that continual ovulation may predispose women to development of apoptotic activity against rapidly growing cancer cells, possesses ovarian cancer. Pregnancy, breast-feeding and oral contraceptive antiangiogenic properties and has been trailed on patients use are protective, but hormone replacement therapy is associated with breast and prostate cancer (Lakhani et al., 2003). On the other with increased risk (Lukanova & Kaaks, 2005; Risch, 1998). hand, 16a-hydroxyestrogens that bind to ERs with lower affinity Although are considered to have an important role in than estradiol are thought to have a carcinogenic influence (Mueck prostate cancer development, animal and human cell culture et al., 2002). studies now suggest a role for estrogens (Bosland, 2004; Harkonen Attention has focused on the estrogen-2,3- and estrogen-3,4- & Makela, 2004). Recent studies with genetically modified mouse quinones because of their ability to act both as electrophiles and models show that malignant changes to the prostate gland are oxidants. As electrophiles, catechol quinones can form covalent dependent on both and estrogen responses, and that adducts with the purine bases adenine and guanine of DNA, these neither hormone alone can produce an aberrant growth pattern depurinating adducts generate apurinic sites that may lead to that leads to malignancy (Bosland, 2004; Risbridger et al., 2003). mutations and in turn cancer. As oxidants, catechol quinines redox P.W. Parodi / International Dairy Journal 22 (2012) 3e14 5 cycle with their semiquinones, producing the superoxide anion and or luteal estrone levels and the risk of breast cancer (Eliassen & reactive oxygen species that may damage lipids and DNA (Cavalieri Hankinson, 2008). et al., 2000; Yager & Davidson, 2006). The proposed ER- and non- Two prospective studies found positive associations between ER-mediated pathways may act in concert in an additive or urinary estrogen levels and risk of postmenopausal breast cancer synergistic manner to cause cancer (Yue et al., 2003). However, (Key et al., 1996; Onland-Moret et al., 2003). However, the rele- under normal physiological conditions deactivation and conjuga- vance of urinary estrogens to functions in target cells is uncertain. tion processes should ensure that insufficient reactive quinines are Seven prospective studies examined associations between either produced to cause significant DNA damage, whereas normal serum or urinary estrogen metabolites and risk of breast cancer in cellular antioxidants should prevent oxidative damage. High levels both pre- and postmenopausal women. These studies measured of hydroxy- and methoxyestrogens are found in blood (Eliasssen, only 2-hydroxyestrone and 16a-hydroxyestrone and overall there Missmer, Tworoger, & Hankinson, 2008) and urine (Eliassen et al., were no statistically significant associations between these two 2009). Indeed, hydroxy- and methoxyestrogens can represent up metabolites or the ratio of 2-hydroxyestrone: 16a-hydroxyestrone to 95% of the total estrogens in normal breast tissue (Castagnetta and the risk of breast cancer (Arslan et al., 2009; Eliassen, Missmer, et al., 2002; Rogan et al., 2003). Overall, no studies have demon- Tworoger, & Hankinson, 2008). strated that estrogen metabolites contribute to cancer in humans (Yager & Davidson, 2006). 3.2. Endometrial cancer

3. Serum estrogen levels and the risk of cancer There has been only one large prospective study on circulating levels and the risk of endometrial cancer (Lukanova Many studies have examined the associations between circu- et al., 2004). This study combined data for postmenopausal lating estrogen levels and the risk of breast, endometrial, ovarian women from the NYUWHS, ORDET and NSHDS cohorts. Estradiol and prostate cancer. Because these cancers produce estrogens and estrone levels were strongly associated with endometrial during their development only studies where blood was drawn cancer risk with RRs of 4.13 (1.76e9.72) and 3.67 (1.71e7.88), prospectively will be considered here. Estradiol circulates bound to respectively. SHBG was negatively associated with risk of endo- carrier proteins with around 70% bound to sex hormone-binding metrial cancer, RR 0.46 (0.02e1.05). globulin (SHBG), which inhibits it bioactivity, and 30% is more loosely bound to albumin. Only about 1% circulates in the free form 3.3. Ovarian cancer (Grow, 2002). Eliassen and Hankinson (2008) recently reviewed seroepidemiology studies of breast, endometrial and ovarian Eliassen and Hankinson (2008) reviewed the few prospective cancer, and the Endogenous Hormones and Prostate Cancer studies that investigated associations between serum sex hormone Collaborative Group (2008) conducted a pooled analysis of 18 concentrations and the risk of ovarian cancer. Overall, there is no prospective studies, which examined the associations between sex convincing evidence for an association between circulating levels of hormone concentrations and the risk of prostate cancer. estrogens or androgens and the risk of ovarian cancer in pre- or postmenopausal women. 3.1. Breast cancer 3.4. Prostate cancer The Endogenous Hormones and Breast Cancer Collaborative Group (2002) analyzed data from nine prospective studies of 663 The Endogenous Hormones and Prostate Cancer Collaborative postmenopausal women who developed breast cancer. The relative Group (2008) conducted a collaborative analysis of worldwide risk (RR) with 95% confidence intervals (CI) for the highest data from 18 cohort studies that investigated the association compared with the lowest quintile of serum estradiol, free estra- between endogenous hormone concentrations and the risk of diol, estrone and was 2.00 (1.47e2.71), 2.58 prostate cancer in 3886 men with incident prostate cancer and (1.76e3.78), 2.19 (1.48e3.22) and 2.00 (1.26e3.16), respectively. For 6438 control subjects. There were no statistical significant associ- SHBG, the RR was 0.66 (0.43e1.00). Since this analysis, results for ations between serum concentrations of any androgens or estradiol combined data from the Swedish Malmo Diet and Cancer Study and the risk of prostate cancer. For estradiol the RR for the highest (MDCS) and the Northern Sweden Health and Disease Study versus lowest level of estradiol was 0.93 (0.77e1.11) and 0.95 (NSHDS), the New York University Women’s Health Study (0.79e1.15) for free estradiol. An investigation of the possibility that (NYUWHS), the Nurses’ Health Study (NHS), and the European a combination of estrogens and androgens may be more strongly Prospective Investigation into Cancer and Nutrition (EPIC), were associated with the risk of prostate cancer than either estrogen or reported and are reviewed by Eliassen and Hankinson (2008) androgen alone, found no evidence of any interaction. Results from the Studies of Hormones and Diet in the Etiology of Breast Tumors (ORDET) were recently reported (Sieri et al., 2009). 4. Relationship between circulating estrogen levels In all these studies, there was roughly a two-fold increase in risk of and levels in breast tissue breast cancer with elevated levels of estrogens. Only a few studies have reported associations between circu- To date, the strongest consistent evidence for a role of circu- lating estrogens and the risk of premenopausal breast cancer. This lating estrogens in cancer is for postmenopausal breast cancer. is undoubtedly due to the difficulty in obtaining a representative However, circulating hormone levels may not reflect hormone sample for menstruating women. Five small studies found no concentrations in target cells. Even so, epidemiological associations association between estrogen levels and the risk of breast cancer. cannot be used to ascribe causality and improved knowledge of Results from two recent large studies indicate that in the EPIC estrogen metabolism at the cellular level is required. cohort there was no association between estradiol or estrone levels Several studies have compared estrogen levels in normal and and the risk of breast cancer. On the other hand, in NHS II there was malignant breast tissue with the levels in blood from pre- and a significant positive association between breast cancer risk and postmenopausal women (Chetrite, Cortes-Prieto, Philippe, Wright, estradiol levels in blood collected during the follicular phase, but & Pasqualini, 2000; Geisler, 2003; van Landeghem, Poortman, not for luteal estradiol. There was no association between follicular Nabuurs, & Thijssen, 1985; Pasqualini et al., 1996; Thijssen, van 6 P.W. Parodi / International Dairy Journal 22 (2012) 3e14

Landeghem, & Poortman, 1986). Even though serum estrogen levels metabolites of the 2- and the 16-hydroxylation pathways were are up to 50-fold lower in postmenopausal than in premenopausal lower, the latter significantly lower. The ratio of 2:16 hydroxylation women, their unconjugated estrogen levels in normal and malig- products was nonsignificantly higher in breast tissue than in urine. nant breast tissue are similar. Estradiol levels are some 2.5-fold There were large inter-individual variations in tissue to urine ratios higher in breast cancer tissue than in normal tissue for both pre- of estrogens and their metabolites. It is possible that not all urinary and postmenopausal women. In breast cancer tissue estradiol estrogens and their derivatives originated from breast tissue. levels are about 10- to 20-fold higher and estrone levels 2- to 10- fold higher than their corresponding serum levels. Available 6. Formation and transformation of tissue estrogen levels studies suggest there is no simple correlation between the levels of in the breast and other estrogen-responsive tissues estrogens in serum and their level in tissue. These data suggest that postmenopausal breast tissue has the ability to selectively accu- There is now substantial evidence that normal and malignant mulate estrogens from the circulation or to synthesize them within breast tissue contains all the necessary steroidogenic enzymes the tissue. necessary for the synthesis of estradiol from circulating inactive androgenic precursors (Labrie, 2003; Labrie et al., 2003; Pasqualini, 5. Relationship between urinary estrogens and estrogen 2004; Perel, Wilkins, & Killinger, 1980). metabolites in breast tissue (DHEA) sulfate (S) is by far the predominant adrenal-derived circulating precursor hormone in men and women. Its concentra- Only one study was found that compared the levels of estrogens tion is from 1000 to 10,000 times higher than that of estradiol and and estrogen metabolites in breast tissue with those in urine. 100e500 times higher than that of . There is also In a small study, Taioli et al. (2010) found that total estrogen considerable estrogen sulfate and lesser amounts of androstene- metabolite levels were similar between breast tissue and urine. dione and in serum. Initially, DHEA-S is converted However, the levels of individual components were quite different to DHEA by the enzyme sulfatase (Fig. 1). DHEA can between the two sources. The sum of estrone and estradiol was then take part in two pathways. Reduction by members of the significantly higher in breast tissue than urine, while the 17b-hydroxysteroid dehydrogenase (17b-HSD) family produces

Fig. 1. Outline of the in situ formation of estrogens from circulating precursors, DHEA-S and estrone sulfate (adapted from Labrie et al., 2003). DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate; 17b-HSD, 17b-hydroxysteroid dehydrogenase; 3b-HSD, 3b-hydroxysteroid dehydrogenase. P.W. Parodi / International Dairy Journal 22 (2012) 3e14 7 androstenediol (17b-HSD types 1,3,5 and 7 are involved in reduc- was significantly associated with increased risk of recurrence and tion reactions, whereas 17b-HSD types 2,4 and 6 are involved in worsened prognosis (Suzuki et al., 2003). oxidation reactions). The enzyme 3b-hydroxysteroid dehydroge- inhibitors blocked the ability of estrogen nase (3b-HSD) converts both DHEA and androstenediol to andros- sulfatase to stimulate the growth of carcinogen-induced mammary tenedione and testosterone, respectively, which, in turn, are tumors in ovariectomized rats (Purohit, Woo, Potter, & Reed, 2000). converted to estrone and estradiol by the aromatase enzyme. The MCF-7 breast cancer cells over-expressing steroid sulfatase injected DHEA / androstenediol, / testosterone and into the flanks of ovariectomized nude mice were used to estrone / estradiol conversions are interconvertable, depending demonstrate the effect of steroid sulfatase inhibitors in reducing on the oxidative/reductive forms of 17b-HSD available, but the steroid sulfatase activity and tumorogenicity (Foster et al., 2006). þ action of aromatase is irreversible. Estrone and estradiol may also A recent initial trial in postmenopausal women with ER metastatic be formed by the action of steroid sulfatase on estrone sulfate and breast cancer demonstrated that a steroid sulfatase inhibitor almost estradiol sulfate, respectively. completely blocked steroid sulfatase activity in peripheral blood Although not studied to the same extent as breast tissue, lymphocytes and tumor tissue (Stanway et al., 2006). A seroepi- endometrial and ovarian tissue also contain a range of steroido- demiology study by Dorgan et al. (1996) did not detect an associ- genic enzymes capable of synthesizing estrogens from circulating ation between serum estrone or estrone sulfate levels and the risk precursors (Ito, Utsunomiya, Yaegashi, & Sasano, 2007; Sasano & of breast cancer. However, the ratio of estrone sulfate to estrone Harada, 1998). The prostate likewise possesses all the necessary was significantly inversely associated with risk, suggesting that enzymes to convert circulating DHEA into estradiol and testos- women who develop breast cancer may be less able to metabolize terone, as well as 5a-reductase to convert testosterone to the more estrone to its inactive form. How estrogen activation and deacti- bioactive (Takase et al., 2006). vation mechanisms in cells become unbalanced is unknown at Normal cells possess mechanisms to ensure estradiol homeo- present. stasis. ER expression in normal breast epithelial cells is inversely related to circulating estradiol levels (Khan et al., 1999; Soderqvist, 7. Breast tissue estrogen content: uptake from the circulation von Schoultz, Tani, & Skoog, 1993). Estrone and estradiol can be versus synthesis in situ converted to inactive sulfates by the action of steroid sulfo- transferase and either excreted from the cell or retained for future Levels of estradiol in normal and in malignant breast tissue are supply of estrone and estradiol. Conjugation of estrone and estra- similar for pre- and postmenopausal women, despite the large diol by uridine diphosphate-glucuronosyltransferases inactivates differences in serum levels (Thijssen et al., 1986; van Landeghem and produces the more soluble estrogen glucuronides that are et al., 1985). High estradiol levels in postmenopausal breast tissue excreted to bile and urine. O-methylation of hydroxyestrogens by may result from enhanced uptake from the circulation or from in COMT and conjugation of estrogen quinones with glutathione situ aromatization of androgens and from estrogen sulfate via the facilitates removal of estrogen metabolites from cells. sulfatase/17b-HSD pathway. It is estimated that about 75% of The expression and level of the various steroidogenic and estrogens in premenopausal women are synthesized in peripheral metabolizing enzymes in each cell of hormone-responsive tissues tissues and close to 100% after menopause (Labrie, 1991, 2003). may influence their estrogen content and potential to transform. However, it is extremely difficult to calculate the relative contri- For instance, a higher activity of the reducing forms of 17b-HSD butions of uptake from the circulation versus in situ synthesis for an may lead to higher levels of estradiol. Aromatase is important for individual organ or tissue, such as the breast. the conversion of androstenedione to estrone and testosterone to A number of lines of indirect evidence suggest a role for in situ estradiol. Aromatase inhibitors were shown to suppress blood and estrogen synthesis in tumor development that include: breast cancer tissue estrogen levels in postmenopausal women by 80e95% (Geisler, 2003). However, in both pre- and postmenopausal The presence of the necessary steroidogenic enzymes in breast breast cancer patients estrone sulfatase activity was found to be tissue (Labrie, 2003; Pasqualini, 2004). 50e200 times higher than aromatase activity, with activity of both Levels of DHEA, the androgen precursor of estrogens, are many- enzymes greater in post- than in premenopausal women fold higher in normal and malignant breast tissue for both pre- (Pasqualini et al., 1996). Enzyme levels were higher in tumors than and postmenopausal women than in their serum (Labrie, 1991; in adjacent tissue, which, in turn, were higher than in normal tissue Thijssen et al., 1986). (Chetrite et al., 2000). Tissue levels of estrone, estradiol and their ER breast tumor tissue contains estradiol (Edery et al., 1981). sulfates reflected the enzyme activities. It is considered that There is little correlation between serum estradiol levels and formation of estradiol from estrone sulfate is far more important breast epithelia proliferation (Khan et al., 1999). than aromatization in breast tissue (Chetrite et al., 2000; Pasqualini et al., 1996; Santner, Feil, & Santen, 1984). Yue, Wang, Hamilton, Demers, and Santen (1998) developed an þ Several lines of evidence suggest that abnormal regulation of animal model where aromatase (A )- and sham (A )-transfected the opposing action of estrogen sulfatases and estrogen sulfo- human MCF-7 breast cancer cells were inoculated into ovariecto- transferases in breast tissue may be responsible for carcinogenesis. mized nude mice, which lack peripheral aromatase activity. With Falany and Falany (1996) found that estrogen sulfotransferase was the injection of androstenedione and the use of Silastic implants to present in human normal mammary epithelial cells, but was produce various estradiol levels, it was determined that under þ absent in ER and ER breast cancer cell lines. Qian, Deng, and physiological conditions, reflecting those in postmenopausal Song (1998) showed that the estrogen-responsive human MCF-7 women, in situ aromatization made a major contribution to estra- breast cancer cell line lacks estrogen sulfotransferase activity. diol levels in breast cancer tissue. Previously, this group showed When this cell line was transfected with estrogen sulfotransferase that rats bearing chemically induced hormone-dependent tumors cDNA, estrogen-stimulated DNA synthesis and cell proliferation synthesized about 25% of their estrogen content in situ by the was inhibited (Qian et al., 1998). Estrogen sulfotransferase estrogen sulfatase pathway (Masamura, Santner, & Santen, 1996). immunoreactivity in human breast carcinoma was significantly A few studies have determined the contribution that local in situ associated with a decreased risk of recurrence or improved estrone synthesis made to the estrogen content of normal and prognosis. On the other hand, steroid sulfatase immunoreactivity malignant breast tissue in postmenopausal women using a double 8 P.W. Parodi / International Dairy Journal 22 (2012) 3e14 isotopic technique. Miller et al. (1998) infused 11 patients with Kensinger (2007) measured individual estradiol levels in milk 14C-labeled estrone and 3H-labeled androstenedione, 18 h before from 206 cows in the Pennsylvania State University dairy herd breast tissue and peripheral blood were taken for analysis. There using RIA. Mean estradiol levels ranged from undetectable (limit of was considerable variation between with the contribution quantification 0.7 pg mL 1) to 22.9 pg mL 1, with a mean value of in situ synthesis ranging from 0 to 75%. In a subsequent study 1.4 0.2 pg mL 1. Twelve samples of milk (4 whole, 5 half- this group measured the percentage contribution of local skimmed, 3 skimmed) were collected from a French supermarket estrone synthesis in both normal and tumor tissue from 24 post- and analyzed using GCeMS/MS (Courant et al., 2007). The sum of menopausal women. Again, there were marked variations between free plus conjugated estradiol ranged from 9.8 to 44.3 pg mL 1, with specimens from different patients and the relative proportion of a mean value of 23.0 pg mL 1. For estrone the corresponding values synthesis to uptake was higher in tumors (0e92%, median value were 75.8e277.5 pg mL 1 and 152.8 pg mL 1, respectively. Eighty 29%) than in normal tissue (0e58%, median value 15%). There was four percent of estradiol and 96% of estrone were present in the a positive correlation between uptake in normal and malignant conjugated form. Vicini et al. (2008) conducted the most compre- tissue (Larionov, Berstein, & Miller, 2002). A small study by Reed hensive survey, with the analysis of 334 samples of retail whole et al. (1989) using a similar isotopic infusion technique found that milk collected from 48 states in the USA during a three-week in 3 of 7 subjects there was no or little in situ formation of estrone. period. RIA, with a sensitivity of 0.8 pg mL 1, was used for the For the other 4 subjects in situ estrone synthesis appeared to assay. The mean value for estradiol was 4.97 0.239 pg mL 1. contribute around 85% of total estrone content in tumor tissue Recently, Farlow et al. (2009) measured estrogen levels in single while the value for normal tissue was 71%. samples of whole, 2% fat and skim milk in the US using LC-MS/MS Breast tissue can also obtain significant quantities of estradiol (limit of quantitation 0.2 pg mL 1). Levels of free estradiol and from infiltrating macrophages. Macrophages are present in normal estrone were 1.0,1.8, and 2.4 pg mL 1 and 10.3, 6.8 and 3.8 pg mL 1, “resting”, pregnant, and lactating breast tissue with levels respectively. Corresponding values for total estradiol and estrone increasing after involution, but probably do not exceed 20% of the were 22.1, 22.2, 20.4 pg mL 1 and 85.5, 84.6, 65.0 pg mL 1, total cell population (Ferguson, 1985). A study by Kelly, Davison, respectively. Bliss, and McGee (1988) found malignant tissue contained the highest concentrations of macrophages with levels around 50% of 8.1. Factors influencing the hormone content of milk the tumor mass. Levels in benign tissue were around one-half this value. Macrophages contain the necessary steroidogenic enzymes, A number of factors can influence the hormone content of milk. including aromatase, to convert the ubiquitous adrenal hormone Both estradiol and estrone levels increase during the estrous cycle, DHEA into estradiol (Mor et al., 1998; Schmidt, Kreutz, Loffler, reaching peak values at estrus, thereafter decreasing to the end of Scholmerich, & Straub, 2000). Estrogen production by macro- the cycle (Gyawu & Pope, 1990; Monk, Erb, & Mollett, 1975). phages is sufficient to stimulate the proliferation of adjacent Hormone levels can also vary with stage of lactation (Gyawu & epithelial cells (Mor et al., 1998). Pope, 1990). There is considerable inter-individual variation within a heard and values for individual cows fluctuate markedly 8. Estrogen content of cows’ milk from week to week (Gyawu & Pope, 1990; Henderson, Karanikolas, Kenealy, & Macmillan, 1994a). Estrogen levels in cows’ milk and factors that influence them The estrogen level in milk increases during pregnancy. have been inadequately studied. The objective of early studies was Henderson et al. (1994a) measured the levels of estrone sulfate in to use estrogen levels as a tool to determine estrus and pregnancy. milk from four herds. Levels rose progressively during pregnancy Early methods that utilized bioassays, colorimetry and spectro- from a mean value of 80e100 pg mL 1 at 60e80 d of pregnancy to fluorimetry were crude and had a high limit of detection. Intro- a plateau value of around 1000 pg mL 1 at 181e200 d. For non- duction of radioimmunoassay (RIA) improved sensitivity, but pregnant cows in the herds, estrone sulfate concentration ranged factors such as loss of hormones during removal of triglycerides, from non-detected to 110 pg mL 1 with a mean value of 59 pg mL 1 cross reactivity of antibodies with other hormones, incomplete Malekinejad et al. (2006) reported that the level of free estrone in of hormone conjugates and lack of pure standards still raw milk from non-pregnant cows and cows in the first, second and affected results. Recently, improvement in extraction techniques third trimester of gestation was 6.2, 9.2, 57 and 118 pg mL 1, coupled with improved RIA assays and measuring techniques like respectively. Corresponding values for free estradiol were 5.6, 10.2, liquid chromatography (LC) or gas chromatography tandem mass 20.4 and 21.3 pg mL 1, respectively. For total estrogens spectrometry (GCeMS/MS) have further advanced sensitivity and (free þ conjugated and for different cows from the above), estrone specificity. However, these techniques are complex, time levels in the first, second and third trimester milk were 7.9, 452 and consuming and expensive, which has limited sample numbers. 1266 pg mL 1, and for estradiol 18.6, 51.4 and 51.2 pg mL 1, Only studies that utilized these improved techniques are reviewed respectively. here. Unfortunately sample sizes for the different types of milk Pape-Zambito et al. (2007) found that mean free estradiol levels were generally small. of milk from non-pregnant cows, early pregnant cows (1e140 d) Hartmann, Lacorn, and Steinhart (1998) measured the hormone and mid-pregnant cows (141e210 d) were 1.3, 0.9 and 3.0 pg mL 1, content of German whole milk (sample numbers unknown) using respectively. In a further study (Pape-Zambito, Magliaro, & GCeMS. The level of total estradiol was less than 20 pg mL 1, which Kensinger, 2008) a group of cows was followed throughout preg- was the limit of detection. Total estrone was present at around nancy. Milk free estrone concentrations averaged 0.6, 7.9 and 130 pg mL 1. Four samples of milk from non-pregnant cows of the 27.1 pg mL 1 during the first, second and third trimester, respec- Utrecht University herd were analyzed by LC-MS/MS. Values for tively. Corresponding values for estradiol were 0.3, 0.9 and free estrone were 23, 22, 27 and 24 pg mL 1, whereas values for 5.0 pg mL 1, respectively. total estrone (free þ conjugated) were 162, 208, 174, and Free estrogens are lipophilic and Pape-Zambito et al. (2008) and 243 pg mL 1. Free estradiol values were 5 pg mL 1, not detected Pape-Zambito, Roberts, and Kensinger (2010) found both estrone (limit of detection 5 pg mL 1), 5 pg mL 1, and not detected, while and estradiol levels were significantly correlated with the fat total estradiol values were 10, 10, 9 and 11 pg mL 1 (Malekinejad, content of whole milk. Malekinejad et al. (2006) found that for 0%, Scherpenisse, & Bergwerff, 2006). Pape-Zambito, Magliaro, and 1.5% and 3.5% fat milk the free estrone content was 8.2, 17.1 and P.W. Parodi / International Dairy Journal 22 (2012) 3e14 9

20.0 pg mL 1, respectively. Corresponding values for estradiol were These values were due largely to the relatively bio-inactive estrone 10.3, 13.9 and 20.6 pg mL 1, respectively. On the other hand, and both estrone and estradiol were predominantly present as another study found no relationship between total estrogen inactive conjugates. Based on recent studies with sensitive assays content and the fat content of milk (Courant et al., 2007). This is (Farlow et al., 2009; Malekiunejad et al., 2006; Pape-Zambito et al., undoubtedly due to the fact that , by far the 2007, 2008, 2010; Vicini et al., 2008), it appears unlikely that free major component of milk estrogens, are more soluble in aqueous estradiol levels in commercial milk would exceed 5.0 pg mL 1. solution. Pasteurization and homogenization of raw milk do not Thus, consumption of 1.5 L of milk or equivalent dairy products per appear to affect the estrogen content (Pape-Zambito et al., 2010). day would result in a daily estradiol intake of not more than 7.5 ng, Ganmaa and Sato (2005), Ganmaa, Wang, Qin, Hoshi, and Sato of which no more than about 0.38 ng would survive first pass (2001), Maruyama, Oshima, and Ohyama (2010), Qin et al. (2004) metabolism to the liver. This value must be considered in the and others have suggested that compared with milk produced 100 context of daily excretion rates for estradiol in humans. In years ago, modern herd bulk milk contains a larger proportion of premenopausal women the daily production of estradiol varies milk from cows in the latter half of pregnancy, and thus has elevated between 0.08 and 1.00 mg, depending upon the phase of the levels of estrogens, which may contribute to reproductive disorders menstrual cycle (Hsueh & Billig, 1995). With the cessation of and cancer at hormone-responsive sites. However, as noted above, ovarian function after menopause, daily estradiol production the increased estrogen levels during late pregnancy is mostly due to decreases to around 12 mg, which is mainly derived from estrone, estrone sulfate, which is largely biologically inactive. In addition, now the predominant estrogen and produced in peripheral tissues during the past 60e70 years milk production per cow has increased tissue from androstenedione by the action of the aromatase about 5-fold due to improved genetics for milk production coupled enzyme (Goldfien & Monroe, 1986). Production rates for estrone with changes in nutritional management (Capper, Cady, & Bauman, range from 40 mgd 1 for slender women to 200 mgd 1 for obese 2009). Estradiol concentrations are negatively correlated with milk women (O’Dell, 1995). In men estradiol production is about yield (Pape-Zambito et al., 2008). This effect is probably due to the 45 mgd 1 (Kaufman & Vermeulen, 2005). Estradiol production in fact that high feed intake increases liver blood flow and metabolic prepubertal children has not been determined directly, but it is clearance rate of estradiol by the liver (Sangsritavong, Combs, considered values will be low (Andersson & Skakkebaek, 1999). Sartori, Armentano, & Wiltbank, 2002). Thus, in the case of premenopausal women, intake of around Pape-Zambito et al. (2008) estimate that the majority of cows 7.5 ng d 1 of estradiol from 1.5 L of milk or equivalent would producing milk for consumption would have less than 2 pg mL 1 of represent merely 0.00076e0.0094% of their daily production and estradiol. This estimate is based on their studies with herd milk and only 5% of this intake would survive the first pass of the liver in milk from pregnant cows and because early lactation cows have a bioactive form. The percentages for postmenopausal women, high milk yields and farmers generally dry off cows at 60 days prepubertal children and men would be higher. before the next expected calving. Thus, there is no evidence that the The Joint FAO/WHO Expert Committee on Food Additives (WHO, levels of estrogen in modern commercial milk are higher than 100 2000) established an acceptable daily intake for estradiol of years ago. 0e50 ng kg 1 of body weight. This figure was based on changes in several hormone-dependent parameters in postmenopausal 9. Absorption and metabolism of estrogens from women. A safety factor of 10 was used to account for normal milk and its products variation among individuals, and an additional factor of 10 was added to protect sensitive individuals. Accordingly, estradiol Estradiol in consumed dairy products is absorbed from the consumption from dairy products should account for only around intestine. The intestinal mucosa contains enzymes capable of the 0.25% of the FAO/WHO upper acceptable daily intake value. transformation of estradiol to estrone and the formation of estrogen Milk contains estrone of which around 90% is estrone sulfate sulfate and glucuronide conjugates. These metabolites and any free (Henderson, Camberis, Simmons, Starrs, & Hardie, 1994b). Estrone estradiol pass to the portal circulation and rapidly pass to the liver has low biological activity and estrone sulfate is inactive. It is where near-complete metabolism to estrone, estrone sulfate (the possible that some of the small quantity of estrone sulfate in milk major conjugate) and some estrogen glucuronides and hydroxyl- that survives metabolism during first pass to the liver may be ated conjugates occurs (Lobo & Cassidenti, 1992; Longcope et al., converted to estrone by sulfatases then to estradiol by 17b-HSD. 1985). Part of the conjugated estrogens pass to the kidneys and However, milk-derived estrones are but a small fraction of a large are excreted in urine. Most of the remainder is excreted with bile to circulating pool. For instance, for postmenopausal women in the the intestinal lumen. Here, some of the conjugated estrogens may be Nurse’s Health study (Hankinson et al., 1995) mean concentrations deconjugated by bacterial b-glucuronidases, but most of these are of estrone and estrone sulfate were 18- and 98-fold higher than re-conjugated by intestinal steroid sulfotransferases and glucur- bioavailable estradiol. In addition, there are vastly higher levels of onosyltransferases and along with the majority of the remaining circulating DHEA-S (Labrie, 2003), and even higher levels in breast bile-derived estrogen conjugates are re-absorbed and pass to the tissue (Thijssen et al., 1986), which can be bioconverted to estrone liver (enterohepatic circulation). A portion escapes this enter- and estradiol if required by the cell. Overall, estrogen-sensitive cells ohepatic circulation and is excreted in the faeces. Any free estradiol possess multiple mechanisms to obtain estradiol for their growth will be conjugated at the next pass of the liver (Adlercreutz & and maintenance and to inactivate surplus to requirements. Martin, 1980; Adlercreutz, Martin, Jarvenpaa, & Fotsis, 1979). Over- Coupled with the relatively minute amount of dairy product- all, it is estimated that as a result of metabolism by the intestinal derived estradiol surviving intestinal absorption and first pass mucosa and first pass to the liver, the bioavailability of oral estradiol liver metabolism, this makes it unlikely that estradiol from this is only in the range of 2e5% (Dusterberg, Schmidt-Gollwitzer, & source would influence cancer development. Humpel, 1985; Kuhnz, Gansau, & Mahler, 1993). As part of a German market basket survey, Hartmann et al. 10. Physiological influence of various exogenous (1998) determined the natural occurrence of steroid hormones in sources of estrogen food. Based on previously published national nutritional data they estimated the daily intake of estrogens (estrone plus estradiol) The estrogen content of milk, its contribution to the body’s from milk products was 0.06 mg for men and 0.05 mg for women. estrogen pool and its physiological significance may be viewed in 10 P.W. Parodi / International Dairy Journal 22 (2012) 3e14

relation to the influence of a number of external factors on serum 0.625 mg d 1 of conjugated equine estrogens (CEE) had serum estrogen levels. Many factors have been studied but BMI appears to estrogen levels measured at baseline and after 1 year of therapy be the most important determinant. Data from the Nurses’ Health (Edlefsen et al., 2010). Estradiol levels increased from 13.3 to Study (Hankinson et al., 1995) showed that in postmenopausal 35.5 pg mL 1, bioavailable estradiol from 8.9 to 16.1 pg mL 1 and women serum estrogen levels were positively associated with BMI. free estradiol from 0.4 to 0.6 pg mL 1. Estrone levels increased from Mean serum estradiol levels ranged from 4.7 pg mL 1 in the lowest 41.4 to 149.9 pg mL 1. After a mean of 10.7 years of follow-up in the quintile of BMI (<21 kg m 2) to 10.0 pg mL 1 in the highest quintile intervention phase of the Women’s Health Initiative randomized (29 kg m 2). For bioavailable estradiol, the corresponding values controlled trial (LaCroix et al., 2011), the hazard ratio for breast were 0.8 and 3.3 pg mL 1. A pooled re-analysis of individual data cancer in postmenopausal women who used 0.625 mg d 1 of CEE from 8 prospective studies showed similar variations (Endogenous for a median of 5.9 years compared to non-users was 0.77 Hormones and Breast Cancer Collaborative Group, 2003). (0.62e0.95) Three other small randomized controlled trials of Dietary components may influence intestinal function and the estrogen-only therapy reviewed by Collins, Blake, and Crosignani bacterial population. Changes in the number of b-glucuronidase- (2005), found no excess risk compared with placebo. Epidemio- producing bacteria can influence deconjugation of estrogens, affect logical evidence from the large Nurses’ Health Study suggested that the enterohepatic circulation and the level of estrogens excreted in women who had undergone a hysterectomy and used estrogen- faeces and urine and their level in blood (Goldin & Gorbach, 1994). only therapy for less than 20 years did not have an increased risk Many studies investigated the role of dietary components such as of developing breast cancer. However, longer duration of usage was þ fat, protein and fiber, on serum estrogen levels, but most suffered associated with higher risk, primarily for ER and progesterone from methodological faults, small sample size and lacked controls. receptor positive breast cancers (Chen et al., 2006). The Nurses’ Health Study found associations between different Use of oral contraceptives by premenopausal women causes dietary patterns and serum estrogen levels in postmenopausal a suppression of ovarian function. As a result the elevated levels of women, but the associations were lost after adjusting for BMI estradiol during mid-cycle and again during the mid-luteal phase (Fung, Hu, Barbieri, Willett, & Hankinson, 2007). The effect of are suppressed several fold to levels at or below levels found in the animal products and their nutrient components on circulating first half of the follicular phase in non-users. A similar suppression estrogens levels in postmenopausal women was investigated in the occurs for estrone (Carr & Bradshaw, 1998; Gaspard, Dubois, Gillian, large Melbourne Collaborative Study (Brinkman et al., 2010). None Franchimont, & Duviver, 1984). In addition, in breast tissue, oral of the food items or nutrients explained more than 1% of the total contraceptive use suppressed estradiol levels 7.8-fold and estrone variation in concentration of any . levels 2.9-fold compared to non-users (O’Brien, Anandjiwala, & For clinical intervention studies, Carruba et al. (2006) random- Price, 1997). However, epidemiological evidence for women using ized postmenopausal women to receive their normal diet or oral contraceptives and were subjected to these large reductions in a traditional Mediterranean diet (intervention). After 6 months, the serum and tissue estrogens does not show a reduced risk for urinary total estrogen concentration in the intervention group subsequent breast cancer (Hunter et al., 2010; Kahlenborn, decreased by 40%. This decrease was largely driven by the estrogen Modugno, Potter, & Severs, 2006). metabolites 2-hydroxy- and 16-ketoestradiol and 17-. Around 30 years ago, several observation studies suggested that Estradiol represented only 1.16% of total estrogens and this level hormonal changes in women might be associated with the risk of was significantly higher than the baseline value. However, during colon cancer. However, the results of these studies were not the study, subjects in the intervention group consumed signifi- consistent. During the period 1961e1990 the sex-specific rates for cantly less calories than at baseline. The intervention group of colon cancer incidence in men increased by 16%, whereas in women postmenopausal women in the large Women’s Health Initiative the incidence declined by 21% (Potter, 1995). This inequality was randomized controlled dietary modification trial consumed a low- considered to be due to hormone differences. HRT use was fat diet with increased intake of fruit, vegetables and grains considered a possible determinant of the beneficial effect in compared to their normal diet. Serum estrogen levels were women, and a number of epidemiological studies investigated this measured in a sub-group of women at baseline and after 1 year of relationship. Hebert-Croteau (1998) conducted a meta-analysis of intervention. Estradiol concentrations decreased from 7.6 to 11 case-control studies, 7 cohort studies and a randomized 6.7 pg mL 1. However, during this period there was a decrease of controlled trial. A summary RR of 0.85 (0.73e0.99) was found 2.4 kg in the weight of women in the intervention group (Prentice between ever versus never users of HRT and the risk of colon et al., 2006). A change in diet to one low in animal fat and refined cancer. The estimated RR was lower among current and recent carbohydrates and rich in low-glycemic-index foods, mono- users, RR 0.69 (0.52e0.91) as compared to short-term users, RR unsaturated and n-3 polyunsaturated fatty acids and phytoes- 0.88 (0.64e1.21). This meta-analysis did not include the 14-year trogens in a small group of postmenopausal women resulted in follow-up data from the large Nurses’ Health Study (Grodstein a fall in serum estradiol levels from 8.62 to 7.07 pg mL 1 after 4.5 et al., 1998), which showed current use of postmenopausal HRT months intervention. During this time, their BMI decreased from was associated with a RR of 0.65 (0.50e0.83). This association was 26.88 to 25.26 kg m 2 (Berrino et al., 2001). attenuated to a RR of 0.84 (0.67e1.05) in past users of HRT. A Based on the limited data available, different dietary patterns subsequent meta-analysis that included the up-dated data from the may be responsible for a 10e20% change in serum estradiol in Nurses’ Health Study (Grodstein, Newcomb, & Stampfer, 1999) postmenopausal women, but about one-half of this effect may be found that women who had ever taken postmenopausal HRT, due to weight change. Similar changes in serum estradiol levels as compared to never users had a RR of 0.80 (0.74e0.86) for colon a result of dietary modification in premenopausal women may also cancer and a RR of 0.81 (0.72e0.92) for rectal cancer. Much of the apply (Goldin et al., 1981). reduction in colorectal cancer was limited to current HRT users (RR, The effect of oral contraceptive use and hormone replacement 0.66, 0.59e0.74). therapy (HRT) on serum and tissue estradiol concentrations is also In the Women’s Health Initiative Randomized Controlled Trial informative and illustrates one of the paradoxes associated with the (Rossouw et al., 2002), the HR for participants who received role of estradiol in cancer development. A sub-group of post- 0.625 mg d 1 CEE plus 2.5 mg d 1 medroxyprogesterone acetate menopausal women in the Women’s Health Initiative randomized compared with placebo was 0.63 (0.43e0.92). On the other hand, in controlled of estrogen therapy that received the CEE-only arm (LaCroix et al., 2011), the HR for CEE compared P.W. Parodi / International Dairy Journal 22 (2012) 3e14 11 with placebo was 1.15 (0.081e1.64). However, the number of colon cannot unequivocally exonerate estrogens in milk and its products cancer cases during the trial was small. A large case-control study as possible carcinogens. by Hoffmeister, Raum, Krtschil, Chang-Claude, and Brenner (2009) found the risk of colorectal cancer decreased in both estrogen-only 11.2. Ovarian cancer therapy, RR 0.42 (0.23e0.78) and in combination therapy, RR 0.60 (0.41e0.87). Genkinger et al. (2006) conducted a pooled analysis of 12 cohort The benefit of estradiol for colorectal carcinogenesis was studies representing 553,217 women among whom 2132 epithelial confirmed in animal studies. For instance, Smirnoff, Liel, Gnainsky, ovarian cancer cases were identified. No associations were Shany, and Schwartz (1999) demonstrated that tumor numbers in observed between intake of specific dairy foods and ovarian cancer ovariectomized mice induced by dimethylhydrazine, were reduced risk. Subsequently, it was also found that there were no associations by 72% when treated with estradiol. Reduced cell growth and between intakes of various dairy foods and the risk of ovarian increased apoptotic activity, in a does-dependent manner, was cancer among participants in the Netherlands Cohort Study on Diet noted in young adult mouse colonocytes when treated with phys- and Cancer (Mommers, Schouten, Goldbohm, & van den Brandt, iological levels of estradiol. In addition, estradiol treatment in 2006). Higher intakes of total dairy foods were associated with ovariectomized mice exhibited a significant protection against a statistically significant decreased risk of ovarian cancer in the preneoplastic lesions (Weige, Allred, & Allred, 2009). Breast Cancer Detection Demonstration Project cohort (Koralek et al., 2006). 11. Epidemiological evidence 11.3. Endometrial cancer Because it is not possible to conduct appropriate clinical trials to The role of dairy products in endometrial cancer has not been prove unequivocally that the small quantity of estrogens in dairy studied widely. A systematic literature review and meta-analysis of products do not influence cancer development, by default, epide- the available evidence by Bandera, Kushi, Moore, Gifkins, and miological studies, despite their limitations, may provide evidence McCullough (2007) found no support for an association between on the safety of dairy product consumption. dairy product consumption and risk of endometrial cancer.

11.1. Breast cancer 11.4. Prostate cancer

Missmer, Smith-Warner, and Spiegelman (2002) conducted The World Cancer Research Fund/American Institute for Cancer a pooled analysis of 8 cohort studies that provided 351,041 subjects, Research (WCRF/AICR) 2007 report on Food, Nutrition, Physical 7379 of whom were diagnosed with breast cancer. No significant Activity and the Prevention of Cancer (The World Cancer Research association was found between dairy product consumption and Fund/American Institute for Cancer Research, 2007) considered breast cancer risk. A review of 10 cohort and 36 case-control studies that there was limited evidence suggesting that high consumption by Moorman and Terry (2004) concluded that the epidemiological of milk and dairy products is a cause of prostate cancer. The WCRF/ evidence did not support a strong association between consump- AICR Panel suggested that high calcium intake from dairy products tion of milk or other dairy products and the risk of breast cancer. In down-regulates the formation of 1,25-dihydroxyvitamin D3 from later major prospective studies McCullough et al. (2005), from the , thereby increasing cell proliferation in the prostate. Cancer Prevention Study II, reported that dairy product consump- Also, consumption of milk products increases blood levels of tion was inversely associated with postmenopausal breast cancer insulin-like growth factor-1, which has been associated with risk. The European Prospective Investigation into Cancer and increased prostate cancer risk in some studies. The Panel did not Nutrition (Pala et al., 2009), which recruited cohorts from 10 implicate estrogens in prostate cancer risk. European countries, did not find dairy product consumption a risk Since the WCRF/AICR report, numerous prospective studies factor for breast cancer. have presented results that included sub-group analyses of asso- Exposure to initiating events during childhood, adolescence and ciations between types of milk and dairy products and stage of early adulthood, when the mammary gland is attaining adult stage prostate cancer. There were often contradictory results, but overall morphology, may influence the risk of breast cancer later in life. the more recent studies do not provide strong support for an A review of 4 case-control and 3 cohort studies (Parodi, 2005) did increased risk of prostate cancer with dairy product consumption not find an association between adolescent dairy product (Parodi, 2009). consumption and subsequent breast cancer development. A later large study of participants from the Nurses’ Health Study and the 11.5. Colon cancer Nurses’ Health Study II found that consumption of whole milk as part of a preschool diet was associated with a slightly decreased Numerous epidemiological studies have demonstrated a nega- risk of adult breast cancer (Michels, Rosner, Chumlea, Colditz, & tive association between dairy product consumption, particularly Willett, 2006). Examination of adolescence diet in the Nurses’ milk, and the risk of colorectal cancer. Huncharek, Muscat, and Health Study II found no overall association for total milk or total Kupelnick (2009) conducted a meta-analysis of 26,335 cases from dairy intake and risk of breast cancer; however, a nonsignificant 60 observational studies. The summary RR for high milk and dairy inverse trend between breast cancer and low-fat milk and low-fat product intake, respectively, on colon cancer risk was 0.78 dairy was noted (Linos, Willett, Cho, & Frazier, 2010). Sixty-five (0.67e0.92) and 0.84 (0.75e0.95). Milk intake was not associated year follow-up of the Boyd Orr cohort showed that a family diet with rectal cancer risk and thus in studies where colorectal cancer rich in dairy products during childhood was not associated with was the end point; summary RR was attenuated to 0.90 (0.81e1.00). adult breast cancer risk (van der Pols et al., 2007). Epidemiology Calcium in milk is believed to be the principal agent responsible for suggests that dairy product consumption during various stages of its protective action (Holt, 2008; Pufulete, 2008), although lipid the life cycle is safe and not associated with a risk of breast cancer. components like conjugated linoleic acid, and sphin- However, because dairy products contain calcium together with gomyelin (Larsson, Bergkvist, & Wolk, 2005; Parodi, 1997) and milk a range of lipid anticancer agents (Parodi, 2005), such analyses proteins, especially whey proteins (Parodi, 2007) may also 12 P.W. Parodi / International Dairy Journal 22 (2012) 3e14 contribute. Whether the small amount of bioactive estradiol in milk Berrino, F., Bellati, C., Secreto, G., Camerini, E., Pala, V., Panico, S., et al. (2001). has any impact on colon carcinogenesis is unknown, but epidemi- Reducing bioavailable sex hormones through a comprehensive change in diet: the Diet and Androgens (DIANA) Randomized Trial. Cancer Epidemiology, ology suggests it causes no harm. Biomarkers and Prevention, 10,25e33. Bosland, M. C. (2004). Sex and prostate carcinogenesis. Annals of the New York Academy of Sciences, 1089,168e176. 12. Conclusions Bradlow, H. I., Telang, N. T., Sepkovic, D. W., & Osborne, M. P. (1996). 2- Hydroxyestrone: the “good” estrogen. Journal of Endocrinology, 150, S259eS265. Brinkman, M. T., Baglietto, L., Krishnan, K., English, D. R., Severi, G., Morris, H. A., Although several lines of evidence suggest a role for estrogens in et al. (2010). Consumption of animal products, their nutrient components and cancer at hormone-responsive sites, such as the breast, ovaries, postmenopausal circulating steroid hormone concentrations. European Journal endometrium and the prostate, the mechanisms remain elusive. of Clinical Nutrition, 64,176e183. This may result from estrogens acting in concert with other Capper, J. L., Cady, R. A., & Bauman, D. E. (2009). The environmental impact of dairy production: 1944 compared with 2007. Journal of Animal Science, 87,2160e2167. hormones, growth factors and cytokines and presents a major Carr, B. R., & Bradshaw, K. D. (1998). Disorders of the ovary and female reproductive research problem. Many studies have determined associations tract. In A. S. Fauci, et al. (Eds.) (14th ed.), Harrison’s principles of internal e between serum estrogen levels and the risk of cancer at estrogen- medicine, Vol. 2 (pp. 2097 2115) New York. NY, USA: McGraw-Hill, Ch. 337. Carruba, G., Granata, O. M., Pala, V., Campisi, I., Agostara, B., Cusimano, R., et al. responsive sites. The association is robust for postmenopausal (2006). A traditional Mediterranean diet decreases endogenous estrogens in breast cancer, but less so for premenopausal women, strong for healthy postmenopausal women. Nutrition and Cancer, 56, 253e259. endometrial cancer and null for ovarian and prostate cancer. Castagnetta, L. A. M., Granata, O. M., Traina, A., Ravizzolo, B., Amoroso, M., Miele, M., et al. (2002). Tissue content of hydroxy estrogens in relation to survival of However, there is no correlation between circulating levels of breast cancer patients. Clinical Cancer Research, 8,3146e3155. estrogens and their precursors with their levels in tissues. It is now Cavalieri, E., Frenkel, K., Liehr, J. G., Rogan, E., & Roy, D. (2000). Estrogens as recognized that the hormone-responsive tissues contain all the endogenous genotoxic agents e DNA adducts and mutations. Journal of the National Cancer Institute Monographs, 27,75e93. necessary steroidogenic enzymes for the synthesis of estrogens Cavalieri, E. L., Devanesan, P., Bosland, M. C., Badawi, A. F., & Rogan, E. G. (2002a). from androgen precursors. In addition, the tissues contain enzymes Catechol estrogen metabolites and conjugates in different regions of the responsible for conjugation of bioactive estrogens to inactive prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer. Carcinogenesis, 23, 329e333. conjugates in order to maintain estradiol homeostasis. Cavalieri, E. L., Li, K.-M., Balu, N., Saeed, M., Devanesan, P., Higginbotham, S., et al. A few studies have measured the contributions of estrogens (2002b). Catechol ortho-quinones: the electrophilic compounds that form from in situ synthesis and uptake from the circulation in normal depurinating DNA adducts and could initiate cancer and other diseases. Carci- e and malignant breast tissue. Results show a large inter-individual nogenesis, 23,1071 1077. Chen, W. Y., Manson, J. E., Hankinson, S. E., Rosner, B., Holmes, M. D., Willett, W. C., variation for in situ synthesis with values ranging from 0 to over et al. (2006). Unopposed estrogen therapy and the risk of invasive breast cancer. 90%, overall values were higher in cancer tissue. Reasons for, and Archives of Internal Medicine, 166, 1027e1032. the significance of, the large variation in source of tissue estrogens, Chetrite, G. S., Cortes-Prieto, J., Philippe, J. C., Wright, F., & Pasqualini, J. R. (2000). Comparison of estrogen concentrations, estrone sulfatase and aromatase in conjunction with a study of the levels and activity of metabo- activities in normal, and in cancerous, human breast tissues. Journal of Steroid lizing enzymes require further investigation. Biochemistry and Molecular Biology, 72,23e27. ’ Cows’ milk contains estrogens. Recent high sensitivity assays Chodosh, L. A., D Cruz, C. M., Gardner, H. P., Ha, S. I., Marquis, S. T., Rajan, J. V., et al. (1999). Mammary gland development, reproductive history, and breast cancer suggest that commercial milk would not contain more than 5 pg mL risk. Cancer Research, 59, 1765se1772s. of free estradiol. On ingestion only 2e5% of this bioactive form Clemons, M., & Goss, P. (2001). Estrogen and the risk of breast cancer. New England survives metabolism in the intestinal mucosa and first pass to the Journal of Medicine, 344,276e285. Collins, J. A., Blake, J. M., & Crosignani, P. G. (2005). Breast cancer risk with post- liver. This amount is only a minute fraction of daily production menopausal hormonal treatment. Human Reproduction Update, 11, 545e560. levels in women and men and is far less than possible fluctuations Courant, F., Antignac, J.-P., Maume, D., Monteau, F., Andre, F., & Le Bizec, B. (2007). in serum levels due to diet, weight excess and use of hormone Determination of naturally occurring oestrogens and androgens in retail samples of milk and eggs. Food Additives and Contaminants, 24,1358e1366. therapy. Expected daily estradiol intake from dairy products Dorgan, J. F., Longcope, C., Stephenson, H. E., Falk, R. T., Miller, R., Franz, C., et al. represents only about 0.25% of the FAO/WHO upper acceptable (1996). Relation of prediagnostic serum estrogen and androgen levels to breast daily intake of exogenous estradiol. Given the multiple mechanisms cancer risk. Cancer Epidemiology, Biomarkers and Prevention, 5,533e539. cells possess to obtain estradiol for their function, it is most unlikely Dusterberg, B., Schmidt-Gollwitzer, M., & Humpel, M. (1985). Pharmacokinetics and biotransformation of in ovariectomized women. 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