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Phyto-oestrogens and breast cancer
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE Phyto-oestrogens and breast cancer SIR—David Ingram and colleagues (Oct 4, p 990)1 report low urinary excretion of two phyto-oestrogens in women with breast cancer and suggest that low intake of these plant-based substances could be causative. This idea fits in with extensive data on low vegetable consumption in women with breast cancer. However, another interpretation is possible. Women who have just been told they have cancer are likely to be anxious; anxious people have fast intestinal transit; and fast intestinal transit reduces absorption from the colon and, specifically, the reabsorption of steroids, which undergo bacterial attack.2 When healthy women with slow colonic transit (whole-gut transit time about 70 h) used a senna laxative or wheat bran for 8 weeks the serum concentrations of oestrone and oestrone sulphate (the most abundant forms of oestrogen in the blood) fell.3 When post-menopausal women swallowed a capsule containing oestradiol glucuronide (with a special coating to delay release to the lower intestine), this oestrogen was measurable in the blood for a shorter period of time when their intestinal transit was speeded up, implying reduced absorption.4 Phyto-oestrogens undergo enterohepatic circulation involving bacterial deconjugation in the colon and are incompletely absorbed before excretion in the urine.5 We suggest that rapid colonic transit can impair phyto-oestrogen absorption, and this could explain low urinary excretion of these substances in women who have just learned that they have cancer. The evidence that phyto-oestrogens are protective against breast cancer is scanty whereas the evidence that increased exposure to endogenous oestrogens is a risk factor is abundant. Because such oestrogens are reabsorbed from the colon and time is a rate-limiting factor for colonic absorption we suggest that habitually slow intestinal transit be investigated as a possible factor for breast cancer. *K W Heaton, S J Lewis Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK 1
Ingram D, Sanders K, Kolybaba M, Lopez D.
THE LANCET • Vol 351 • January 10, 1998
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Case-control study of phyto-oestrogens and breast cancer. Lancet 1997; 350: 990–94. Marcus SN, Heaton KW. Intestinal transit, deoxycholic acid and the cholesterol saturation of bile—three inter-related factors. Gut 1986; 27: 550–58. Lewis SJ, Heaton KW, Oakey RE, McGarrigle HHG. Lower serum oestrogen levels associated with faster intestinal transit. Br J Cancer 1997; 76: 395–400. Lewis SJ, Oakey RE, Heaton KW. Effect of altering intestinal transit time on absorption of exogenous oestrogen. Eur J Gastroenterol Hepatol (in press). Adlercreutz H, Mazur W. Phyto-oestrogens and western diseases. Ann Med 1997; 29: 95–120.
SIR—We agree with David Ingram and colleagues 1 that measurement of phytooestrogens in the body reflects bioavailability closely but biological markers have their own problems. The inter-assay coefficient of variation ranged between 11% and 43%, one of the phyto-oestrogens (genistein) could not be measured, and the completeness of urine collection, which may have been different for cases and controls, was not assessed. Moreover, it is not clear whether the laboratory technicians were blind to the disease status of the participants. Urinary phyto-oestrogens measure short-term dietary intake, and it is not known how representative the diet around the time of the urine collection was of the diet during the aetiologically relevant period many years before the onset of the disease. Participants completed a food-frequency questionnaire but it is unclear to which time window the questions related. Were women asked about their diet during the 3-day period of urine collection or their usual diet some years before the diagnosis of breast cancer (or equivalent time in the controls)? The intake of fruit, vegetables, fibre, or soya-containing foods should have been reported. Although the levels of urinary nitrogen were the same in cases and controls, the cases may have been eating less healthily secondary to worry about their disease. This possibility could have been eliminated if phytooestrogens had been measured in all women who attended the clinic with a suspicion of breast cancer and if it had been shown that those whose diagnosis was not subsequently confirmed had higher levels of urinary phytooestrogens than those who were found
to have breast cancer. The refusal rate in the controls was more than 50%. Cases were highly motivated probably because of their disease status, and, therefore, willing to comply with the high demands of three consecutive 24 h urine collections. This was not true for the eligible controls. It is likely that the controls who participated were unrepresentative of the population from which the cases derived. The lay press has been active in advising people to consume more phyto-oestrogen-containing foods. Bread enriched with soya and linseed was first launched in Australia and New Zealand among promotional claims that phyto-oestrogens could protect against breast cancer. Perhaps eligible controls susceptible to this campaign were especially motivated to participate in the study. *Punam Mangtani, Isabel dos Santos Silva Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 1
Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997; 350: 990–94.
SIR—David Ingram and colleagues1 suggest that there is a substantial reduction in breast-cancer risk among women with a high intake of phytooestrogens. The method they used to avoid recording bias in the dietary information was well-designed but there are other possible biases. Although a family history of breast cancer was assessed in the interview, no data are in the article. A positive family history of breast cancer (especially first-degree) is associated with a 2–3-fold increase in the risk.2,3 Since the prevalence of this risk factor in the population is about 10%4 heterogeneity of the groups in respect of family history could confound the results of the study. A family history of breast cancer is a strong predictor of health concern, and women with such a history are more likely to follow the lay media recommendations regarding screening procedures and a healthier diet. Also, such women might be more likely to volunteer for studies such as Ingram’s. A movement towards increased consumption of phyto-
137
COMMENTARY
CORRESPONDENCE Phyto-oestrogens and breast cancer SIR—David Ingram and colleagues (Oct 4, p 990)1 report low urinary excretion of two phyto-oestrogens in women with breast cancer and suggest that low intake of these plant-based substances could be causative. This idea fits in with extensive data on low vegetable consumption in women with breast cancer. However, another interpretation is possible. Women who have just been told they have cancer are likely to be anxious; anxious people have fast intestinal transit; and fast intestinal transit reduces absorption from the colon and, specifically, the reabsorption of steroids, which undergo bacterial attack.2 When healthy women with slow colonic transit (whole-gut transit time about 70 h) used a senna laxative or wheat bran for 8 weeks the serum concentrations of oestrone and oestrone sulphate (the most abundant forms of oestrogen in the blood) fell.3 When post-menopausal women swallowed a capsule containing oestradiol glucuronide (with a special coating to delay release to the lower intestine), this oestrogen was measurable in the blood for a shorter period of time when their intestinal transit was speeded up, implying reduced absorption.4 Phyto-oestrogens undergo enterohepatic circulation involving bacterial deconjugation in the colon and are incompletely absorbed before excretion in the urine.5 We suggest that rapid colonic transit can impair phyto-oestrogen absorption, and this could explain low urinary excretion of these substances in women who have just learned that they have cancer. The evidence that phyto-oestrogens are protective against breast cancer is scanty whereas the evidence that increased exposure to endogenous oestrogens is a risk factor is abundant. Because such oestrogens are reabsorbed from the colon and time is a rate-limiting factor for colonic absorption we suggest that habitually slow intestinal transit be investigated as a possible factor for breast cancer. *K W Heaton, S J Lewis Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK 1
Ingram D, Sanders K, Kolybaba M, Lopez D.
THE LANCET • Vol 351 • January 10, 1998
2
3
4
5
Case-control study of phyto-oestrogens and breast cancer. Lancet 1997; 350: 990–94. Marcus SN, Heaton KW. Intestinal transit, deoxycholic acid and the cholesterol saturation of bile—three inter-related factors. Gut 1986; 27: 550–58. Lewis SJ, Heaton KW, Oakey RE, McGarrigle HHG. Lower serum oestrogen levels associated with faster intestinal transit. Br J Cancer 1997; 76: 395–400. Lewis SJ, Oakey RE, Heaton KW. Effect of altering intestinal transit time on absorption of exogenous oestrogen. Eur J Gastroenterol Hepatol (in press). Adlercreutz H, Mazur W. Phyto-oestrogens and western diseases. Ann Med 1997; 29: 95–120.
SIR—We agree with David Ingram and colleagues 1 that measurement of phytooestrogens in the body reflects bioavailability closely but biological markers have their own problems. The inter-assay coefficient of variation ranged between 11% and 43%, one of the phyto-oestrogens (genistein) could not be measured, and the completeness of urine collection, which may have been different for cases and controls, was not assessed. Moreover, it is not clear whether the laboratory technicians were blind to the disease status of the participants. Urinary phyto-oestrogens measure short-term dietary intake, and it is not known how representative the diet around the time of the urine collection was of the diet during the aetiologically relevant period many years before the onset of the disease. Participants completed a food-frequency questionnaire but it is unclear to which time window the questions related. Were women asked about their diet during the 3-day period of urine collection or their usual diet some years before the diagnosis of breast cancer (or equivalent time in the controls)? The intake of fruit, vegetables, fibre, or soya-containing foods should have been reported. Although the levels of urinary nitrogen were the same in cases and controls, the cases may have been eating less healthily secondary to worry about their disease. This possibility could have been eliminated if phytooestrogens had been measured in all women who attended the clinic with a suspicion of breast cancer and if it had been shown that those whose diagnosis was not subsequently confirmed had higher levels of urinary phytooestrogens than those who were found
to have breast cancer. The refusal rate in the controls was more than 50%. Cases were highly motivated probably because of their disease status, and, therefore, willing to comply with the high demands of three consecutive 24 h urine collections. This was not true for the eligible controls. It is likely that the controls who participated were unrepresentative of the population from which the cases derived. The lay press has been active in advising people to consume more phyto-oestrogen-containing foods. Bread enriched with soya and linseed was first launched in Australia and New Zealand among promotional claims that phyto-oestrogens could protect against breast cancer. Perhaps eligible controls susceptible to this campaign were especially motivated to participate in the study. *Punam Mangtani, Isabel dos Santos Silva Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 1
Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997; 350: 990–94.
SIR—David Ingram and colleagues1 suggest that there is a substantial reduction in breast-cancer risk among women with a high intake of phytooestrogens. The method they used to avoid recording bias in the dietary information was well-designed but there are other possible biases. Although a family history of breast cancer was assessed in the interview, no data are in the article. A positive family history of breast cancer (especially first-degree) is associated with a 2–3-fold increase in the risk.2,3 Since the prevalence of this risk factor in the population is about 10%4 heterogeneity of the groups in respect of family history could confound the results of the study. A family history of breast cancer is a strong predictor of health concern, and women with such a history are more likely to follow the lay media recommendations regarding screening procedures and a healthier diet. Also, such women might be more likely to volunteer for studies such as Ingram’s. A movement towards increased consumption of phyto-
137