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Milk Estrogen on Cancer Risk

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Milk Estrogen on Cancer Risk International Dairy Journal 22 (2012) 3e14 Contents lists available at SciVerse ScienceDirect International Dairy Journal journal homepage: www.elsevier.com/locate/idairyj Review Impact of cows’ milk estrogen on cancer risk Peter W. Parodi* Human Nutrition and Health Research, Dairy Australia, Melbourne, Australia article info abstract Article history: Estrogens have been implicated in cancer at hormone-responsive sites, such as the breast, 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 estradiol levels. Hormone-responsive and many Accepted 14 August 2011 peripheral cells contain all the necessary steroidogenic enzymes 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. Breast cancer . .........................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 antiestrogen 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 cell 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 estrone. 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 enzyme 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 ovulation and decreases serum estrogen levels results in be oxidized further to reactive catechol estrogen 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 glutathione 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 progesterone, 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 estriol (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.
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