Effect of Energy Deficiency on Estrogen Metabolism in Premenopausal Women
Effect of Energy Deficiency on Estrogen Metabolism in Premenopausal Women
Purpose: Physical activity has been associated with decreased breast cancer risk, potentially through changes in estrogen metabolism. Two-hydroxyestrone (2-OHE1) and 16α-hydroxyestrone (16α-OHE1) have different biological properties, and the ratio of these metabolites (2/16) has been proposed to predict breast cancer risk. Diet and exercise have been found to influence estrogen metabolism, particularly when a state of negative energy balance is achieved. We sought to determine whether 4 months of moderate-intensity exercise coupled with calorie restriction would result in changes in urinary 2-OHE1, 16α-OHE1, or 2/16 in sedentary, premenopausal, eumenorrheic women.
Methods: Average age was 31.5 yr, average body fat was 31.6%, and average BMI was 23.7. Urinary estrogen metabolites were measured in 24 women during the baseline and for four intervention months in the midfollicular and midluteal phases.
Results: The intervention produced a significant drop in body fat (4.5%) and body weight (3.7 kg). Aerobic fitness increased significantly (26%; P < 0.001). Overall, there were no significant effects of the diet and exercise intervention on 2-OHE1, 16α-OHE1, or 2/16. However, when divided into tertiles according to baseline 2/16, the intervention resulted in significant increases in 2/16 in women in the lowest tertile. Women in the lowest tertile (average 2/16 = 0.91) did not differ from the other tertiles in baseline estradiol concentrations, body fat, weight, fitness, or changes in these variables with the intervention.
Conclusion: The data suggest that women at higher risk for developing breast cancer because of low 2/16 may reduce their risk by participating in lifestyle interventions such as exercise/calorie restriction.
A growing body of evidence suggests that being physically active reduces a woman's risk for developing breast cancer. To date, the mechanism for this reduction in risk remains unknown. One biologically plausible hypothesis that has been suggested is that exercise results in lower estrogen levels, and estrogens are strongly implicated in the etiology of breast cancer. In general, however, the levels of physical activity that have been observed to result in breast cancer risk reduction are unlikely to result in decreases in circulating estrogens. Moreover, occupations that require more physical activity also have been associated with decreased breast cancer risk and are unlikely to result in a decrease in circulating estrogen concentrations. It is also now generally accepted that exercise interventions that lead to changes in circulating estrogens in premenopausal women must be accompanied by an energy deficit such that the energy expenditure of exercise is not matched by increased food intake. Thus, exercise itself is not viewed as a mechanism to modulate the central control of the reproductive axis and the ovarian output of estrogen.
Given that the levels of physical activity reported to decrease breast cancer risk are unlikely to incur an energy deficit and are, therefore, unlikely to result in decreased circulating estrogens, it may be speculated that exercise, with or without energy deficiency, exerts more subtle changes in estrogen metabolism-that is, an increase in the proportion of estrogen metabolized through the 2-hydroxylation pathway and a reduction through the 16α-hydroxylation pathway-and perhaps it is this change that results in lowered breast cancer risk. Estrogen is primarily metabolized in humans through these two major competing pathways to yield two hydroxylated metabolites. These two metabolites, 2-hydroxyestrone (2-OHE1) and 16α-hydroxyestrone (16α-OHE1), exhibit very different biological activities. 16α-OHE1 has been shown to be estrogenic, is able to form covalent bonds with the estrogen receptor, and has been associated with breast cancer in humans and mammary tumor development in animal models. 2-OHE1, in contrast, seems to display no, or antiestrogenic, activity, and increased levels have been associated with decreased breast cancer incidence in animal models. Further, lifestyle interventions that have been implicated in reducing breast cancer risk, such as altering dietary consumption of cruciferous vegetables and soy, seem to increase 2-hydroxylation and the ratio of 2-OHE1/16α-OHE1 (2/16).
Because of their competitive production and their different biological properties, it has been proposed that the ratio of 2/16 may be a marker for breast cancer risk, with a higher 2/16 being associated with a decreased risk. This relationship has been found in many but not all studies. We propose that exercise and/or energy deficiency increases the ratio of 2/16, and this, in turn, is a factor in the physical activity-mediated reduction in breast cancer risk.
Early studies have suggested that athletes have higher 2-OHE1 levels than sedentary women. Further, a case study that involved brief bouts of exercise training reported increases in estrogen 2-hydroxylation. More recently, Bentz et al. have reported that premenopausal women with higher self-reported physical activity levels had higher 2/16 levels than women who reported less physical activity. Campbell et al., however, found that maximal oxygen consumption, a measure of aerobic fitness, was unrelated to 2-OHE1, 16α-OHE1, or the ratio of 2/16. To date, only one study has been published in which estrogen metabolites were measured in response to an exercise intervention. In that study, Atkinson et al. report that estrogen metabolism was generally unaltered in postmenopausal women who exercised 5 d·wk for 1 yr, although changes in intraabdominal fat tended to be associated with changes in 2-OHE1 and 2/16.
To our knowledge, there are no data on the effects of exercise training, with or without weight loss, on estrogen metabolites in premenopausal women. Although the majority of breast cancers develop in women after menopause, the potential to impact risk factors earlier in life may have important implications for lifelong risk. Therefore, the purpose of the present study was to determine the effect of moderate exercise training combined with calorie restriction on 2-OHE1, 16α-OHE1, and the ratio of 2/16. The exercise training and calorie-restriction program was designed so that the subjects would lose body weight and body fat and would increase aerobic capacity (VO2max).
Purpose: Physical activity has been associated with decreased breast cancer risk, potentially through changes in estrogen metabolism. Two-hydroxyestrone (2-OHE1) and 16α-hydroxyestrone (16α-OHE1) have different biological properties, and the ratio of these metabolites (2/16) has been proposed to predict breast cancer risk. Diet and exercise have been found to influence estrogen metabolism, particularly when a state of negative energy balance is achieved. We sought to determine whether 4 months of moderate-intensity exercise coupled with calorie restriction would result in changes in urinary 2-OHE1, 16α-OHE1, or 2/16 in sedentary, premenopausal, eumenorrheic women.
Methods: Average age was 31.5 yr, average body fat was 31.6%, and average BMI was 23.7. Urinary estrogen metabolites were measured in 24 women during the baseline and for four intervention months in the midfollicular and midluteal phases.
Results: The intervention produced a significant drop in body fat (4.5%) and body weight (3.7 kg). Aerobic fitness increased significantly (26%; P < 0.001). Overall, there were no significant effects of the diet and exercise intervention on 2-OHE1, 16α-OHE1, or 2/16. However, when divided into tertiles according to baseline 2/16, the intervention resulted in significant increases in 2/16 in women in the lowest tertile. Women in the lowest tertile (average 2/16 = 0.91) did not differ from the other tertiles in baseline estradiol concentrations, body fat, weight, fitness, or changes in these variables with the intervention.
Conclusion: The data suggest that women at higher risk for developing breast cancer because of low 2/16 may reduce their risk by participating in lifestyle interventions such as exercise/calorie restriction.
A growing body of evidence suggests that being physically active reduces a woman's risk for developing breast cancer. To date, the mechanism for this reduction in risk remains unknown. One biologically plausible hypothesis that has been suggested is that exercise results in lower estrogen levels, and estrogens are strongly implicated in the etiology of breast cancer. In general, however, the levels of physical activity that have been observed to result in breast cancer risk reduction are unlikely to result in decreases in circulating estrogens. Moreover, occupations that require more physical activity also have been associated with decreased breast cancer risk and are unlikely to result in a decrease in circulating estrogen concentrations. It is also now generally accepted that exercise interventions that lead to changes in circulating estrogens in premenopausal women must be accompanied by an energy deficit such that the energy expenditure of exercise is not matched by increased food intake. Thus, exercise itself is not viewed as a mechanism to modulate the central control of the reproductive axis and the ovarian output of estrogen.
Given that the levels of physical activity reported to decrease breast cancer risk are unlikely to incur an energy deficit and are, therefore, unlikely to result in decreased circulating estrogens, it may be speculated that exercise, with or without energy deficiency, exerts more subtle changes in estrogen metabolism-that is, an increase in the proportion of estrogen metabolized through the 2-hydroxylation pathway and a reduction through the 16α-hydroxylation pathway-and perhaps it is this change that results in lowered breast cancer risk. Estrogen is primarily metabolized in humans through these two major competing pathways to yield two hydroxylated metabolites. These two metabolites, 2-hydroxyestrone (2-OHE1) and 16α-hydroxyestrone (16α-OHE1), exhibit very different biological activities. 16α-OHE1 has been shown to be estrogenic, is able to form covalent bonds with the estrogen receptor, and has been associated with breast cancer in humans and mammary tumor development in animal models. 2-OHE1, in contrast, seems to display no, or antiestrogenic, activity, and increased levels have been associated with decreased breast cancer incidence in animal models. Further, lifestyle interventions that have been implicated in reducing breast cancer risk, such as altering dietary consumption of cruciferous vegetables and soy, seem to increase 2-hydroxylation and the ratio of 2-OHE1/16α-OHE1 (2/16).
Because of their competitive production and their different biological properties, it has been proposed that the ratio of 2/16 may be a marker for breast cancer risk, with a higher 2/16 being associated with a decreased risk. This relationship has been found in many but not all studies. We propose that exercise and/or energy deficiency increases the ratio of 2/16, and this, in turn, is a factor in the physical activity-mediated reduction in breast cancer risk.
Early studies have suggested that athletes have higher 2-OHE1 levels than sedentary women. Further, a case study that involved brief bouts of exercise training reported increases in estrogen 2-hydroxylation. More recently, Bentz et al. have reported that premenopausal women with higher self-reported physical activity levels had higher 2/16 levels than women who reported less physical activity. Campbell et al., however, found that maximal oxygen consumption, a measure of aerobic fitness, was unrelated to 2-OHE1, 16α-OHE1, or the ratio of 2/16. To date, only one study has been published in which estrogen metabolites were measured in response to an exercise intervention. In that study, Atkinson et al. report that estrogen metabolism was generally unaltered in postmenopausal women who exercised 5 d·wk for 1 yr, although changes in intraabdominal fat tended to be associated with changes in 2-OHE1 and 2/16.
To our knowledge, there are no data on the effects of exercise training, with or without weight loss, on estrogen metabolites in premenopausal women. Although the majority of breast cancers develop in women after menopause, the potential to impact risk factors earlier in life may have important implications for lifelong risk. Therefore, the purpose of the present study was to determine the effect of moderate exercise training combined with calorie restriction on 2-OHE1, 16α-OHE1, and the ratio of 2/16. The exercise training and calorie-restriction program was designed so that the subjects would lose body weight and body fat and would increase aerobic capacity (VO2max).