Effects of exercise dose on endogenous estrogens in postmenopausal women: a randomized trial

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Cancer Epidemiology and Prevention Research, Departments of Oncology and Community Health Sciences, Keck School of Medicine, School of Public Health, Cross Cancer Institute, Faculty of Physical Education and Recreation, CancerControl Alberta, Alberta Health Services, 2210 2nd Street Southwest, Calgary, Alberta, Canada T2S 3C3

Free access

Exercise dose comparison trials with biomarker outcomes can identify the amount of exercise required to reduce breast cancer risk and also strengthen the causal inference between physical activity and breast cancer. The Breast Cancer and Exercise Trial in Alberta (BETA) tested whether or not greater changes in estradiol (E2), estrone, and sex hormone-binding globulin (SHBG) concentrations can be achieved in postmenopausal women randomized to 12 months of HIGH (300 min/week) vs MODERATE (150 min/week) volumes of aerobic exercise. BETA included 400 inactive postmenopausal women aged 50–74 years with BMI of 22–40 kg/m2. Blood was drawn at baseline and 6 and 12 months. Adiposity, physical fitness, diet, and total physical activity were assessed at baseline and 12 months. Intention-to-treat analyses were performed using linear mixed models. At full prescription, women exercised more in the HIGH vs MODERATE group (median min/week (quartiles 1,3): 253 (157 289) vs 137 (111 150); P<0.0001). Twelve-month changes in estrogens and SHBG were <10% on average for both groups. No group differences were found for E2, estrone, SHBG or free E2 changes (treatment effect ratios (95% CI) from linear mixed models: 1.00 (0.96–1.06), 1.02 (0.98–1.05), 0.99 (0.96–1.02), 1.01 (0.95, 1.06), respectively, representing the HIGH:MODERATE ratio of geometric mean biomarker levels over 12 months; n=382). In per-protocol analyses, borderline significantly greater decreases in total and free E2 occurred in the HIGH group. Overall, no dose effect was observed for women randomized to 300 vs 150 min/week of moderate to vigorous intensity exercise who actually performed a median of 253 vs 137 min/week. For total and free E2, the lack of differential effect may be due to modest adherence in the higher dose group.

Abstract

Exercise dose comparison trials with biomarker outcomes can identify the amount of exercise required to reduce breast cancer risk and also strengthen the causal inference between physical activity and breast cancer. The Breast Cancer and Exercise Trial in Alberta (BETA) tested whether or not greater changes in estradiol (E2), estrone, and sex hormone-binding globulin (SHBG) concentrations can be achieved in postmenopausal women randomized to 12 months of HIGH (300 min/week) vs MODERATE (150 min/week) volumes of aerobic exercise. BETA included 400 inactive postmenopausal women aged 50–74 years with BMI of 22–40 kg/m2. Blood was drawn at baseline and 6 and 12 months. Adiposity, physical fitness, diet, and total physical activity were assessed at baseline and 12 months. Intention-to-treat analyses were performed using linear mixed models. At full prescription, women exercised more in the HIGH vs MODERATE group (median min/week (quartiles 1,3): 253 (157 289) vs 137 (111 150); P<0.0001). Twelve-month changes in estrogens and SHBG were <10% on average for both groups. No group differences were found for E2, estrone, SHBG or free E2 changes (treatment effect ratios (95% CI) from linear mixed models: 1.00 (0.96–1.06), 1.02 (0.98–1.05), 0.99 (0.96–1.02), 1.01 (0.95, 1.06), respectively, representing the HIGH:MODERATE ratio of geometric mean biomarker levels over 12 months; n=382). In per-protocol analyses, borderline significantly greater decreases in total and free E2 occurred in the HIGH group. Overall, no dose effect was observed for women randomized to 300 vs 150 min/week of moderate to vigorous intensity exercise who actually performed a median of 253 vs 137 min/week. For total and free E2, the lack of differential effect may be due to modest adherence in the higher dose group.

Introduction

Inadequate physical activity is one of the few known modifiable risk factors for postmenopausal breast cancer (World Cancer Research Fund and American Institute for Cancer Research 2007, 2010). Minimum physical activity recommendations for cancer prevention include 150 min/week (World Health Organization 2011, Kushi et al. 2012) or 210 min/week of moderate-intensity activity (World Cancer Research Fund and American Institute for Cancer Research 2007), 150 min/week of moderate-vigorous activity (Canadian Society for Exercise Physiology 2011), and 75 min/week of vigorous activity (World Health Organization 2011, Kushi et al. 2012). Whether or not these recommendations are optimal for postmenopausal breast cancer prevention, however, is unclear (Hastert et al. 2013). Recently a meta-analysis estimated a 5% decrease in breast cancer risk with every 2 h/week increment in moderate-vigorous recreational activity (Wu et al. 2013). Such analyses of observational data could be misleading, however, because of inconsistent methods for defining physical activity across studies, physical activity measurement error, and confounding by other factors. Alternatively, exercise trials with biomarker endpoints provide important evidence (Rundle 2005).

Endogenous estrogens are convincing biomarkers of postmenopausal breast cancer risk (Key et al. 2002, Woolcott et al. 2010, James et al. 2011, Tworoger et al. 2011, 2014, Zhang et al. 2013, Endogenous Hormones and Breast Cancer Collaborative Group 2015). One pooled analysis showed an approximately twofold higher risk of postmenopausal breast cancer for women categorized in the highest vs lowest quintiles of circulating estradiol (E2) and estrone concentrations respectively (Endogenous Hormones and Breast Cancer Collaborative Group 2015). Most randomized controlled trials (RCTs) comparing 3–12 month exercise prescriptions of 150–225 min/week vs no exercise in postmenopausal women have improved circulating concentrations of E2, estrone, and sex hormone-binding globulin (SHBG) on average by 2–13% (Figueroa et al. 2003, Copeland & Tremblay 2004, McTiernan et al. 2004, Orsatti et al. 2008, Monninkhof et al. 2009, Friedenreich et al. 2010, Yoo et al. 2010, Campbell et al. 2012, Kim & Kim 2012). Additional mechanisms are hypothesized to relate physical activity to breast cancer risk (reviewed in Neilson et al. (2014)); however, with the exception of body fat (World Cancer Research Fund and American Institute for Cancer Research 2007, 2010 Suzuki et al. 2009), these pathways are not as clearly established as for sex hormones.

Previously in the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) trial, we randomized 320 postmenopausal women to 225 min/week of aerobic exercise or usual inactivity over 12 months. In the exercise group, average reductions in circulating E2 and free E2, and the average increase in SHBG, were significantly greater than controls; there was no significant difference for estrone changes (Friedenreich et al. 2010). Furthermore in an exploratory analysis, favorable dose–response trends were found between average E2 changes (but not estrone) and exercise adherence: <150, 150–225 and >225 min/week. However, the ALPHA trial was not designed to examine dose–response trends. Our dose–response analysis was based on self-selected adherence levels, and we had insufficient statistical power for detecting significant differences across adherence strata.

In the Breast Cancer and Exercise Trial in Alberta (BETA), we aimed to formally test the dose–response effects of exercise by examining whether or not greater changes in E2, estrone, and SHBG concentrations would be achieved in postmenopausal women randomized to a HIGH (300 min/week) vs MODERATE (150 min/week) volume aerobic exercise prescription over 12 months.

Materials and methods

The BETA trial

Detailed methods for the BETA trial were published previously (Friedenreich et al. 2014). The BETA trial was a two-centre, two-armed randomized controlled exercise intervention trial in Calgary and Edmonton, Alberta, conducted between June 2010 and June 2013. The overall aim of the study was to examine the dose–response effects of aerobic exercise on adiposity and a variety of proposed blood biomarkers of postmenopausal breast cancer risk. We hypothesized that more favorable biomarker improvements would occur in women prescribed a higher vs moderate volume of aerobic exercise. The focus of the current report is on endogenous sex hormones, which were secondary outcomes from the trial. Total body fat change was the primary outcome and is described in a separate report (Friedenreich et al. 2015).

Participants

Eligible women were postmenopausal, age 50–74 years, BMI 22–40 kg/m2 and moderately inactive (≤120 min/week of self-reported moderate-intensity recreational activity or ≤3 days/week for <30 min/session maximum; estimated VO2max ≤34.5 ml/kg min or 34.6 ml/kg min ≤VO2max ≤37.0 ml/kg min and 7-day accelerometer count<10 000 steps/day), with no previous cancer diagnosis except non-melanoma skin cancer and no major co-morbid condition or recent major reconstructive surgery. Women were able to maintain acceptable heart and lung function in a sub-maximal treadmill test, were non-users of exogenous hormones or drugs affecting estrogen metabolism and non-smokers, consumed less than or equal to two drinks of alcohol/day over the past year, were English-speaking, resided in Calgary or Edmonton with access to our fitness facility, were not intending to be away more than 4 weeks consecutively and 8 weeks total over the next year and not on or planning a weight loss program. The study protocol was approved by the Alberta Cancer Research Ethics Committee and the Conjoint Health Research Ethics Board of the University of Calgary and the Health Research Ethics Board of the University of Alberta. All participants provided written informed consent after full explanation of the purpose of the trial and trial procedures. Trial registration on ClinicalTrials.gov was initiated prior to analyzing any primary or secondary outcomes.

Randomization

Four hundred postmenopausal women were randomly assigned in a 1:1 ratio to either a 12-month aerobic exercise intervention of HIGH (300 min/week) or MODERATE (150 min/week) volume. Randomization was stratified by the study centre and BMI (<28.8, ≥28.8). Blocking was used within strata with block sizes of four or six to ensure balance between the two arms with respect to the number of participants. The random allocation sequence was generated via user-defined functions within R Software (version 2.11) (R Core Team 2010). Allocations were concealed in numbered envelopes that were prepared by a staff member unrelated to the study team.

Measurements

Demographic and baseline health information was collected by a questionnaire when ascertaining eligibility. Past year total physical activity, which was the sum of all occupational, household, and recreational activities as well as walking or bicycling to/from work (Friedenreich et al. 2006), and past year usual diet (Csizmadi et al. 2007) were self-reported at baseline and 12 months. All activities reported in the Past Year Total Physical Activity Questionnaire were converted into the metabolic equivalent of task (MET) h/week per year using the Compendium of Physical Activities (Ainsworth et al. 2011). Additionally at baseline and 12 months, submaximal fitness tests were conducted using the same protocols and equipment at both study centers. In Edmonton, fitness tests took place at the Cross Cancer Institute and the Behavioural Medicine Fitness Centre at the University of Alberta. Calgary participants were assessed at the Tom Baker Cancer Centre and the Faculty of Kinesiology, University of Calgary. Fitness testing followed the multistage modified Balke treadmill test protocol (Pollock et al. 1982). Testing was complete once a participant reached 85% of her age-predicted maximum heart rate or volitional exhaustion. Each participant's predicted VO2max was estimated using the multistage model and the American College of Sports Medicine metabolic equations for maximum oxygen consumption (American College of Sports Medicine 2000).

Anthropometric measurements were taken at the same time as fitness testing. Standing height and weight were measured by research staff using a balance beam scale and stadiometer. Measures were taken in duplicate and then averaged; if the two measures were discrepant, a third measure was taken. Waist circumference was determined using an anthropometric measuring tape and the National Institutes for Health protocol (National Institutes of Health 1998, Canadian Society for Exercise Physiology 2003). Full body dual-energy x-ray absorptiometry (DXA) scans were taken using a Hologic Discovery A DXA system and Hologic QDR Software (Hologic Inc., Bedford, MA, USA) or a GE Healthcare Lunar Prodigy DXA and GE Healthcare enCORE Software (GE Medical Systems Lunar, Madison, WI, USA) to assess lean mass and total fat mass. Percent body fat was calculated as 100%×(fat mass/(fat mass+lean mass)).

Intervention

The intervention began with a goal to reach full exercise prescription within the first 12 weeks by gradually increasing exercise volume. As previously described (Friedenreich et al. 2014), the goal by week 13 was to attain 5 days/week of aerobic exercise for 30 min (MODERATE) or 60 min (HIGH) per session achieving 60–80% maximum heart rate reserve for at least half of each workout. The individual target intensity ranged from 60–70% to 70–80% heart rate reserve depending on ability level. To confirm this intensity, women were asked to wear Polar FT4 heart rate monitors (Polar Electro, Lachine, QC, Canada) during supervised and unsupervised sessions. Between weeks 13 and 52, women were prescribed supervised sessions at an exercise facility 3 days/week and unsupervised home-based exercise 2 days/week. Supervised sessions took place at the Westside Recreation Centre (Calgary) and the Behavioural Medicine Fitness Centre, University of Alberta (Edmonton). Home-based sessions were initially prescribed once weekly (weeks 5–8) and later increased to twice weekly. Adherence was monitored using weekly exercise logs maintained by participants, documenting activity types, total exercise duration, exercise ‘time in zone,’ average heart rate, and a Borg Rating of Perceived Exertion (Borg 1998). Exercise trainers kept separate logs of the same exercise variables as well as any absences from supervised sessions. Participants were asked not to change their usual diet.

Endogenous sex hormones

Blood samples were drawn at baseline and 6 and 12 months after a minimum 10 h fast and complete abstinence from exercise and alcohol intake for 24 h. If a woman was <55 years of age with no bilateral oophorectomy or menopausal status was uncertain, a follicle-stimulating hormone test confirmed eligibility. All blood samples were stored at −86 °C in the Alberta Cancer Research Biorepository in Calgary. E2 and estrone were measured by radioimmunoassay with preceding organic solvent extraction and Celite column partition chromatography steps. Assay sensitivities were 2 and 4 pg/ml, respectively, and inter-assay coefficients of variation (CV) were 9–14%. SHBG was measured using solid-phase, two-site chemiluminescent immunometric assays on the Immulite analyzer (Siemens Healthcare Diagnostics, Deerfield, IL, USA); assay sensitivity was 1 nmol/l and the inter-assay CV was <10%. Appropriate quality control samples were used to monitor assay reliability. Each participant's baseline and 6 and 12 month samples were analyzed in the same batch and each batch included an equal number of MODERATE and HIGH blood samples. Blind duplicates were included in and between batches to estimate CVs. All lab personnel were blinded to the intervention assignment.

Sample size/power considerations

Sample size calculations were based on the standard formula for two-sample mean comparisons (Rosner 2011) with α=0.05 (two-sided) for comparing mean 12-month biomarker changes (log-transformed) with no adjustment for baseline values. ALPHA trial results provided standard deviation estimates and yardstick intervention effects. A sample size of 150 participants per group was initially selected allowing 95% power to detect 3 and 4% group differences in 12-month changes in percent body fat and total fat mass, respectively, which were primary outcomes in the trial. Allowing 10% loss to follow-up, a group size of 165 was planned. However, due to a high volunteer response, the sample size was increased to 200 per group.

Statistical analysis

Group differences in demographic and lifestyle information and biomarker concentrations at baseline were compared using a χ2 test for categorical data, t-test for continuous data and Wilcoxon rank-sum test for non-normally distributed continuous data. Because all biomarker data were non-normally distributed, subsequent analyses of a more analytic (rather than descriptive) nature were performed on log-transformed values. Sex hormone changes in the two arms were compared in an intention-to-treat analysis using linear mixed models that accounted for repeated measures of sex hormone concentrations at 6 and 12 months and adjusted for baseline levels of the biomarker of interest as a covariate. Treatment effect ratios, also referred to as ‘treatment effects’ or ‘dose effects’ in this report, were calculated from these models and represented the HIGH:MODERATE ratio of geometric mean biomarker levels over 12 months (reflecting changes from baseline to 6 and 12 months). A treatment effect ratio <1.0 indicated lower biomarker concentrations in the HIGH exercise group compared with the MODERATE group at 6 and 12 months; a ratio >1.0 indicated lower biomarker concentrations in the MODERATE exercise group; and a ratio equal to 1.0 indicated no difference in biomarker concentrations between exercise groups.

In addition, we repeated our intention-to-treat analysis stratified by a priori effect modifiers: baseline BMI and study site (Calgary, Edmonton) and also by baseline physical fitness level in a post hoc analysis (given effect modification by this variable in the ALPHA trial (Friedenreich et al. 2011)). Furthermore, a sensitivity analysis was performed to account for possible sex hormone hemodilution that might occur as a result of a larger body surface area in obese women (Yang et al. 2011). In so doing, we repeated the intention-to-treat analysis, with and without stratification by baseline BMI, using sex hormone mass as the unit of analysis. Sex hormone mass was calculated as (log(sex hormone concentration)×((weight (kg)0.425×height (m)0.725×0.2025)×1.395)) as described previously (Grubb et al. 2009, Yang et al. 2011) using a plasma volume (L) formula (i.e., body surface area (m2)×1.395) derived for women (Pearson et al. 1995). An additional sensitivity analysis was performed removing non-compliant participants who changed energy intake ≥1000 kcal/day between baseline and 12 months according to Diet History questionnaires.

In addition, a per-protocol analysis was conducted for women who were 90–100% adherent in the MODERATE group (135–150 min/week) or ≥90% adherent in the HIGH group (≥270 min/week) on average between weeks 13 and 52 (after the 12-week ramp-up period) according to exercise logs. Furthermore an exploratory analysis was performed, categorizing women by quintiles of total exercise duration without regard to group randomization. The ratio of geometric means (12 months:baseline) was calculated for each quintile and statistical significance was determined from linear models adjusted for the baseline level of the biomarker of interest. Tests for linear trend treated categories as a continuous variable. Moreover, a per-protocol analysis was carried out stratifying by time in zone (average, weeks 13–52) to explore the possibility of enhanced dose effects when exercise was mainly of high intensity. Finally, Spearman correlation coefficients (rs) were used to describe relations between 12-month changes in each biomarker and hypothesized mediators of change (changes in VO2max and adiposity respectively) (Friedenreich et al. 2011). All statistical tests were two-sided with a 0.05 level of significance. Analyses were conducted using SAS version 9.2 (SAS Institute, Cary, NC, USA).

Results

A total of 400 women were randomized (Fig. 1) as described previously (Friedenreich et al. 2015). Baseline characteristics pertaining to the sex hormones analysis are described in Table 1. At baseline, 22, 40, and 38% of women in the HIGH volume group were BMI <25 kg/m2, 25≤BMI<30 kg/m2 and BMI ≥30 kg/m2, respectively, and similarly for the MODERATE group (19, 42, and 39% respectively). Participants on average were younger postmenopausal women and overweight; most had post-secondary education, were not employed full-time and self-identified as white. There were no group differences at baseline except for average SHBG levels, which were significantly higher in the HIGH volume group. Fourteen women dropped out; nine from the MODERATE arm and five from the HIGH arm (Fig. 1). An additional four women with total E2 ≥66 pg/ml were suspected as perimenopausal or using estrogen treatment and were therefore excluded. No serious adverse events were reported during the trial.

Figure 1
Figure 1

CONSORT diagram: Flow of participants through the BETA trial, Alberta, Canada, 2010–2013.

Citation: Endocrine-Related Cancer 22, 5; 10.1530/ERC-15-0243

Table 1

Baseline characteristics of randomized participants in the BETA trial, Alberta, Canada, 2010–2013

Baseline characteristicModerateHigh
n (%)n (%)
No.200200
Full-time employment59 (30)71 (36)
Education
 ≤High school45 (23)45 (23)
 College/Trade63 (32)58 (29)
 Undergraduate degree54 (27)59 (30)
 Graduate degree38 (19)38 (19)
Marital status
 Married/Common in law139 (70)136 (68)
 Other61 (30)64 (32)
Race/Ethnicity
 White186 (93)172 (86)
 Other14 (7)28 (14)
Family history of breast cancer
 ≥1 first-degree family member39 (20)33 (17)
 None161 (80)166 (83)
Ever used hormone therapy55 (28)62 (31)
History of hysterectomy36 (18)44 (22)
Mean±s.d.Mean±s.d.
Age (years)59.5±5.159.4±4.8
Maximal oxygen consumption (ml/kg/min)26.8±5.026.7±5.0±5.3
BMI (kg/m2)29.4±4.429.1±4.4
Body weight (kg)77.4±13.077.3±13.0
Percent body fat (%)40.7±5.940.5±5.8
Waist circumference (cm)98.6±10.898.7±11.0
Median (quartiles 1,3)Median (quartiles 1,3)
Total energy intake (kcal/day) 1414 (1112, 1789)1379 (1001, 1797)
Alcohol intake (g/day) 2.4 (0.7, 7.8)3.0 (0.9, 6.4)
Past year total physical activity (MET-h/week)
 Total activity90.6 (60.6, 121.9)89.0 (62.2, 115.8)
 Occupational activity25.9 (4.5, 55.2)34.2 (2.6, 56.3)
 Household activity41.0 (27.0, 60.6)40.4 (28.3, 60.1)
 Recreational activity7.6 (2.3, 13.0)6.9 (2.4, 13.3)
Sex hormone concentration
 Estradiol (pg/ml)9.7 (7.6, 12.9) 9.4 (7.3, 12.2)
 Estrone (pg/ml)39.0 (30.9, 47.3) 37.0 (30.7, 43.7)
 Sex hormone binding globulin (nmol/l)a42.7 (32.8, 59.7)46.1 (34.7, 65.4)
 Free estradiol (pg/ml)0.22 (0.17, 0.32)0.21 (0.15, 0.29)
Sex hormone massb
 Estradiol (ng)24.0 (18.4, 34.4) 23.1 (17.9, 31.3)
 Estrone (ng)97.8 (75.5, 126.5) 92.3 (75.2, 113.8)
 Sex hormone-binding globulin (nmol) 106.8 (84.5, 145.5)122.4 (89.7, 164.8)
 Free estradiol (ng)0.57 (0.43, 0.81)0.53 (0.39, 0.75)

There were no statistically significant differences at baseline between HIGH and MODERATE groups for these variables except for sex hormone binding globulin, P=0.04.

Estimated as (log(sex hormone concentration)×((weight (kg)0.425×height (m)0.725×0.2025)×1.395)) as described previously (Grubb et al. 2009, Yang et al. 2011) using a plasma volume (L) formula (i.e., body surface area (m2)×1.395) derived for women (Pearson et al. 1995).

Some exercise adherence data from BETA have been described previously (Friedenreich et al. 2015). For women included in the sex hormones analysis, those in the HIGH vs MODERATE group recorded more exercise on average (P<0.0001, two-sample t-test), with 12-month median (quartiles 1,3) adherence values of 228 (156 262) and 129 (106 138) min/week, respectively. Between weeks 13 and 52 (at full prescription after the 12-week ramp-up period), median adherence was 253 (157 289) vs 137 (111 150) min/week, and median time in zone was 128 (66 185) vs 88 (54 115) min/week, respectively, for the HIGH and MODERATE groups (P<0.0001). Based on the Past Year Total Physical Activity Questionnaire (Friedenreich et al. 2006), usual recreational activity increased by 4.0 and 2.0 h/week (240 and 120 min/week) for HIGH and MODERATE groups, respectively (P<0.0001; Table 2). Women in the HIGH group on average experienced significantly greater reductions in percent body fat compared with the MODERATE group (Friedenreich et al. 2015). On average, total energy intake decreased significantly in the MODERATE group over 12 months, but not significantly more than in the HIGH group (Table 2).

Table 2

Physical activitya, fitness, diet, and adiposity changes (12 months – baseline) by group assignment in the BETA trial, Alberta, Canada, 2010–2013

MeasureMODERATEHIGHBetween-groupPb
nMean change95% CInMean change95% CI
Total activity (h/week)1842.1−0.2, 4.41853.20.9, 5.50.51
Total activity (MET-h/week)18416.79.4, 23.918526.819.4, 34.20.05
Occupational activity (h/week)1840.8−0.8, 2.5185−0.03−1.8, 1.70.48
Occupational activity (MET-h/week)1843.7−1.2, 8.51852.0−3.6, 7.70.67
Household activity (h/week)184−0.7−2.4, 1.1185−0.8−2.3, 0.80.92
Household activity (MET-h/week)184−0.8−6.1, 4.5185−1.7−5.9, 2.50.78
Recreational activity (h/week)1842.01.4, 2.51854.03.4, 4.6<0.0001
Recreational activity (MET-h/week)18413.811.4, 16.318526.523.6, 29.4<0.0001
Maximal oxygen consumption (ml/kg/min)1754.03.3, 4.81805.04.2, 5.90.09
Total energy intake (kcal/day)184−79.1−136.0, −21.9189−51.0−108.0, 5.90.49
Alcohol intake (g/day)1840.0−0.9, 1.01890.0−0.7, 0.60.88
Body weight (kg)c183−1.9−2.4, −1.3190−2.6−3.2, −1.90.11
Percent body fatc185−1.1−1.5, −0.7190−2.0−2.5, −1.50.003
Waist circumference (cm)c183−4.7−5.6, −3.9190−6.0−7.1, −4.90.06

MET, metabolic equilvalent of task.

Estimated using the Past Year Total Physical Activity Questionnaire (Friedenreich et al. 2006).

Based on a two-sample t-test.

Detailed analyses of adiposity change are described elsewhere (Friedenreich et al. 2015).

At 6 and 12 months, all biomarker changes were <10% (Table 3) and, unexpectedly, were more favorable for the MODERATE vs HIGH volume group. However, results from linear mixed models suggested no significant group differences with respect to biomarker changes, with all treatment effect ratios approximately equal to 1.0. Stratifying the results by baseline BMI, study site, or estimated VO2max still resulted in non-significant dose effects for all biomarkers except SHBG, which varied by baseline BMI. Specifically, obese women experienced significantly greater SHBG increases with the HIGH prescription (12-month increase of 13.1% vs 8.2% for the MODERATE group; between-group P=0.03 from linear mixed models), whereas non-obese women experienced significantly greater increases with the MODERATE prescription (12-month change of 10.6% vs 2.4% for the HIGH group; between-group P=0.02). Intention-to-treat and BMI-stratified results were essentially unchanged when based on biomarker mass instead of biomarker concentration. Results were also unchanged when ten women with 12-month changes ≥1000 kcal/day in dietary energy intake were excluded.

Table 3

Changes in endogenous estrogen and SHBG concentrations over 12 months in the BETA trial, Alberta, Canada, 2010–2013

Sex hormoneBaseline6 months12 monthsTreatment effectaBetween-groupPb
Geometric mean95% CIGeometric mean95% CIPercent changecGeometric mean95% CIPercent changecRatio of HIGH:MOD95% CI
Estradiol (pg/ml)
 MODERATE9.99.3, 10.59.79.1, 10.2−2.49.58.9, 10.1−4.51.000.96, 1.060.90
 HIGH9.48.9, 9.99.59.0, 10.00.49.18.6, 9.6−3.6
Estrone (pg/ml)
 MODERATE38.636.7, 40.638.236.3, 40.2−1.237.435.6, 39.3−3.21.020.98, 1.050.42
 HIGH36.434.8, 38.036.835.1, 38.51.136.434.7, 38.20.1
SHBG (nmol/l)
 MODERATE43.240.6, 46.046.243.5, 49.06.847.444.6, 50.49.60.990.96, 1.020.58
 HIGH47.644.7, 50.850.247.1, 53.45.350.747.7, 53.96.4
Free estradiol (pg/ml)
 MODERATE0.230.22, 0.250.220.21, 0.24−4.50.210.20, 0.23−7.51.010.95, 1.060.83
 HIGH0.210.20, 0.230.210.20, 0.22−1.30.200.19, 0.21−5.5

SHBG, sex hormone binding globulin.

HIGH:MODERATE ratio of geometric means for biomarker levels over 12 months, adjusted for biomarker level at baseline. A ratio <1.0 indicates lower biomarker concentrations in the HIGH exercise group at 6 and 12 months; a ratio >1.0 indicates lower biomarker concentrations in the MODERATE exercise group; a ratio equal to 1.0 indicates no difference in biomarker concentrations between the HIGH and MODERATE exercise groups. Sample sizes were n=189 for MODERATE and n=193 for HIGH groups.

P for testing group difference over 12 months from the linear mixed model, adjusted for biomarker level at baseline.

Percent hormone change at 6 or 12 months from baseline for that group.

Scatter plots of individual biomarker changes against exercise adherence (data not shown) revealed non-adherence in some participants such that 24% of the women in the HIGH group (n=48) exercised ≤150 min/week on average over 12 months; in the MODERATE group 3% of the women exercised >150 min/week. Therefore, a per-protocol analysis was done based on exercise minutes per week (Table 4). In the per-protocol sample, all biomarker 12-month changes were <14% and treatment effect ratios were not significantly different from 1.00. However, total and free E2 reductions were slightly greater for the HIGH vs MODERATE group resulting in borderline significant dose effects (between-group P=0.09 and P=0.06 respectively). In an exploratory analysis, inverse dose–response trends were found between decreasing total and free E2 concentrations and increasing quintiles of total exercise time (Table 5). The highest 12-month reductions in total and free E2 concentrations were −11.0 and −13.7%, respectively, for women with average adherence estimates >245 min/week, although similar reductions were also observed in the second and third quartiles.

Table 4

Changes in endogenous estrogen and SHBG concentrations over 12 months in adherent womena in the BETA trial, Alberta, Canada, 2010–2013

Sex hormoneBaseline6 months12 monthsTreatment effectbBetween-groupPc
Geometric mean95% CIGeometric mean95% CIPercent changedGeometric mean95% CIPercent changedRatio of HIGH:MOD95% CI
Estradiol (pg/ml)
 MODERATE10.29.2, 11.410.29.1, 11.3−0.769.68.5, 10.9−6.20.930.86, 1.010.09
 HIGH8.88.2, 9.58.78.0, 9.4−0.857.97.3, 8.5−10.6
Estrone (pg/ml)
 MODERATE38.735.3, 42.338.634.9, 42.7−0.1336.933.6, 40.7−4.51.010.96, 1.070.66
 HIGH34.632.4, 36.935.532.9, 38.32.633.631.5, 36.0−2.8
SHBG (nmol/l)
 MODERATE44.940.3, 50.047.642.9, 52.96.149.444.5, 54.910.11.020.96, 1.080.45
 HIGH48.343.4, 53.853.247.8, 59.110.152.647.5, 58.39.0
Free estradiol (pg/ml)
 MODERATE0.240.21, 0.270.230.21, 0.26−2.70.210.19, 0.24−9.20.930.85, 1.000.06
 HIGH0.200.18, 0.220.190.17, 0.21−4.20.170.16, 0.19−13.2

SHBG, sex hormone binding globulin.

Included the subgroup of women for whom, across weeks 13–52 (at full prescription), average adherence in the exercise logs was 90–100% in the MODERATE group (135–150 min/week; n=57) or ≥90% in the HIGH group (270–350 min/week; n=78).

HIGH:MODERATE ratio of geometric means for biomarker levels over 12 months, adjusted for biomarker level at baseline. A ratio <1.0 indicates lower biomarker concentrations in the HIGH exercise group at 6 and 12 months; a ratio >1.0 indicates lower biomarker concentrations in the MODERATE exercise group; a ratio equal to 1.0 indicates no difference in biomarker concentrations between the HIGH and MODERATE exercise groups.

P for testing group difference over 12 months from the linear mixed model, adjusted for biomarker level at baseline.

Percent hormone change at 6 or 12 months from baseline for that group.

Table 5

Hormone concentrations at baseline and 12 months by quintile of exercise adherencea for MODERATE and HIGH groups combined

Sex hormoneBaseline12 Months12 Months:BaselinebPercent changecP valuedP-trende
Geometric meanb95% CIGeometric meanb95% CIGeometric mean ratio 95% CI
Estradiol (pg/ml)
 ≤110 min/week10.39.3, 11.410.89.8, 12.01.060.98, 1.145.2Ref0.002
 110–134 min/week9.68.8, 10.58.98.2, 9.80.930.88, 0.99−7.10.002
 134–152 min/week10.29.3, 11.29.38.4, 10.40.920.86, 0.99−8.30.003
 152–245 min/week9.48.6, 10.39.68.9, 10.41.020.94, 1.11.90.19
 >245 min/week8.88.2, 9.57.87.2, 8.40.890.84, 0.95−11.0<0.0001
Estrone (pg/ml)
 ≤110 min/week40.537.5, 43.739.236.0, 42.70.970.91, 1.03−3.1Ref0.97
 110–134 min/week37.434.5, 40.535.833.0, 38.80.960.91, 1.00−4.40.40
 134–152 min/week38.535.6, 41.638.635.6, 41.81.000.95, 1.060.30.51
 152–245 min/week36.533.9, 39.437.334.7, 40.11.020.96, 1.092.00.43
 >245 min/week34.632.4, 37.033.731.5, 36.10.970.93, 1.02−2.50.44
Sex hormone binding globulin (nmol/l)
 ≤110 min/week44.039.9, 48.647.042.4, 52.21.071.01, 1.136.9Ref0.37
 110–134 min/week44.640.5, 49.247.943.6, 52.71.071.02, 1.137.40.83
 134–152 min/week42.238.4, 46.446.742.6, 51.21.111.06, 1.1610.80.36
 152–245 min/week48.543.5, 54.151.146.3, 56.31.051.01, 1.095.20.95
 >245 min/week48.143.2, 53.552.747.6, 58.31.101.05, 1.159.50.26
Free estradiol (pg/ml)
 ≤110 min/week0.240.21, 0.270.250.22, 0.281.030.95, 1.122.7Ref0.002
 110–134 min/week0.220.2, 0.250.200.18, 0.220.910.86, 0.96−9.30.004
 134–152 min/week0.240.22, 0.270.210.19, 0.240.890.83, 0.96−11.60.003
 152–245 min/week0.210.19, 0.230.210.19, 0.231.000.93, 1.090.50.28
 >245 min/week0.200.18, 0.220.170.15, 0.190.860.81, 0.93−13.7<0.0001

Quintile split groups with n=76, 76, 78, 76, and 76 for five groups based on the exercise adherence levels ≤110, 110–134, 134–152, 152–245, >245 min/week, respectively, using average adherence from exercise logs, weeks 1–52.

Values are unadjusted.

Percentage hormone change at 12 months from baseline for that level of adherence.

P-values for hormone change at 12 months from baseline between controls and that level of adherence, adjusted for the baseline value. Ref, referent group.

Trend analysis for hormone change at 12 months from baseline between controls and three adherence groups, adjusted for the baseline value.

In a per-protocol analysis examining exercise intensity (Table 6), women who exercised ≥60% of their prescribed exercise duration in their target heart rate zone (i.e., at least 90 min/week in the MODERATE group or at least 180 min/week in the HIGH group time in zone) experienced stronger dose effects with respect to total and free E2 changes (11.2–13.5% 12-month decreases in the HIGH group vs 2.3–5.6% in the MODERATE group; P=0.03, P=0.01 between groups for total and free E2, respectively). However, E2 was also reduced with less time in zone (12-month decreases of 10.1–12.9% for the HIGH group; 14.9–17.2% for MODERATE). Among all participants, 12-month body weight changes correlated significantly with biomarker changes (rs=0.21, P<0.0001 for total E2; rs=0.17, P<0.0009 for estrone; rs=−0.44, P<0.0001 for SHBG; rs=0.29, P<0.0001 for free E2). Correlations with percent body fat change were somewhat weaker (rs=0.13, P=0.01 for total E2; rs=0.08, P=0.12 for estrone; rs=−0.27, P<0.01 for SHBG; rs=0.17, P<0.01 for free E2). Change in waist circumference was significantly correlated with SHBG and free E2 changes (SHBG: rs=−0.27, P<0.0001; free E2: rs=0.14, P=0.007) but not total E2 (rs=0.09, P=0.09) or estrone (rs=0.04, P=0.49). Similarly, changes in estimated VO2max were weakly correlated with changes in SHBG (rs=0.11, P=0.04) and free E2 (rs=−0.11, P=0.04) but not total E2 (rs=−0.09, P=0.08) or estrone (rs=0.02, P=0.64).

Table 6

Changes in endogenous estrogen and SHBG concentrations over 12 months in adherent womena stratified by time at target intensity; the BETA trial, Alberta, Canada, 2010–2013

BiomarkerPrescribed exercise durationn6 month percent change from baseline12 month percent change from baselineTreatment effectbBetween-groupPc
Proportion of time at high intensity (average min/week)dRatio of HIGH:MOD95% CI
Estradiol (pg/ml)
 <60% prescribedMODERATE17−13.4−14.91.070.96, 1.200.23
HIGH44−0.8−10.1
 ≥60% prescribedMODERATE405.2−2.30.880.79, 0.990.03
HIGH34−1.0−11.2
Estrone (pg/ml)
 <60% prescribedMODERATE17−7.5−8.61.091.00, 1.180.06
HIGH442.2−4.0
 ≥60% prescribedMODERATE403.2−2.70.990.91, 1.070.74
HIGH343.2−1.1
SHBG (nmol/l)
 <60% prescribedMODERATE1710.49.51.000.90, 1.110.93
HIGH4410.49.0
 ≥60% prescribedMODERATE404.310.31.040.97, 1.130.27
HIGH349.78.9
Free estradiol (pg/ml)
 <60% prescribedMODERATE17−16.0−17.21.070.95, 1.210.26
HIGH44−4.4−12.9
 ≥60% prescribedMODERATE403.6−5.60.860.77, 0.970.01
HIGH34−4.0−13.5

Included n=135 women for whom, across weeks 13–52 (at full prescription), average adherence in the exercise logs was 90–100% in the MODERATE group (135–150 min/week; n=57) or ≥90% in the HIGH group (≥270 min/week; n=78).

HIGH:MODERATE ratio of geometric means for biomarker levels over 12 months adjusted for biomarker level at baseline. A ratio <1.0 indicates lower biomarker concentrations in the HIGH exercise group at 6 and 12 months; a ratio >1.0 indicates lower biomarker concentrations in the MODERATE exercise group; a ratio equal to 1.0 indicates no difference in biomarker concentrations between the HIGH and MODERATE exercise groups.

P for testing the HIGH-MODERATE group difference over 12 months from the linear mixed model, adjusted for biomarker level at baseline.

Time at high intensity was defined as time exercising at an intensity of 60–80% heart rate reserve averaged for each participant over 52 weeks. Cut points for the stratified analysis were 60% of the prescribed durations, i.e., 90 min/week in the MODERATE group and 180 min/week in the HIGH group.

Discussion

On average, circulating concentrations of total E2, estrone, SHBG, and free E2 changed similarly over 12 months for women prescribed 150 or 300 min/week of aerobic exercise. Treatment effect ratios, representing the HIGH:MODERATE ratio of geometric mean biomarker levels over 12 months, were all null, providing no evidence of a dose effect on circulating estrogen or SHBG concentrations. Exploratory analyses suggested our null findings may be partly adherence related and, possibly, that dose effects might vary with baseline BMI and when exercise is done mainly with vigorous intensity.

Compared with the ALPHA trial, which tested an exercise prescription of 225 min/week using similar methods and participants (Friedenreich et al. 2010), estrogen reductions in BETA were smaller on average (4–8% in BETA vs 12–13% in ALPHA for free and total E2; 0–3% in BETA vs 5% in ALPHA for estrone) and SHBG increases were slightly larger in BETA (6–10% in BETA vs 3% in ALPHA). Similarly, other exercise trials in postmenopausal women typically improved these biomarker concentrations by 2–13% (Figueroa et al. 2003, Copeland & Tremblay 2004, McTiernan et al. 2004, Orsatti et al. 2008, Monninkhof et al. 2009, Friedenreich et al. 2010, Yoo et al. 2010, Campbell et al. 2012, Kim & Kim 2012). Thus, despite the relatively high exercise prescription in BETA, we could not demonstrate greater estrogen or SHBG changes than reported previously in similar trials. The reasons for this finding are unclear but might relate to modest adherence, particularly in the high volume group.

Epidemiologic research has generally shown that exercise-induced changes in estrogen concentrations are attributable to weight loss in postmenopausal women (Friedenreich et al. 2011, Campbell et al. 2012, Stolzenberg-Solomon et al. 2012, Jones et al. 2013). Adipose tissue becomes a major site of estrone and E2 biosynthesis after menopause via aromatase activity (Folkerd & Dowsett 2013, Kinoshita et al. 2014), and consequently, BMI relates positively to circulating E2 and estrone concentrations (Endogenous Hormones and Breast Cancer Collaborative Group 2015). Furthermore, BMI is inversely related to SHBG concentrations (Endogenous Hormones and Breast Cancer Collaborative Group et al. 2011, Goto et al. 2014), which restrict E2 bioavailability through SHBG binding (our analysis of free E2 therefore reflects the bioavailable portion). The significant correlations we observed in BETA between E2 and body weight changes, and between SHBG and changes in body weight and waist circumference, are consistent with a mediating role for adiposity. For unknown reasons, adiposity correlations were not found with estrone.

It is unclear, then, why we did not find significant dose effects despite greater fat loss with the 300 min/week prescription (Table 2). It is possible that because the magnitude of the difference in fat loss between the two groups was rather low (∼1% difference between groups with respect to total fat loss), there were limited effects on sex hormones. Similarly, there may have been insufficiently large group differences with respect to other mediating factors besides adiposity, e.g., insulin mediating SHBG levels (Pugeat et al. 1991). Another explanation relates to hemodilution of sex hormone concentrations in obesity (Grubb et al. 2009, Yang et al. 2011). If the body surface area was decreased through weight loss in our trial, then decreased vascular volume would manifest through increased sex hormone concentrations, thereby confounding our primary analysis. However, a sensitivity analysis based on biomarker mass made essentially no difference in our primary results or in our stratified analyses of obese women.

There may also have been effect modification. For instance, our finding of stronger SHBG increases with the 300 min/week prescription in obese women might reflect the stronger reductions in subcutaneous abdominal fat we observed in this subgroup (Friedenreich et al. 2015), which could mediate SHBG changes (Liedtke et al. 2012). We cannot explain why greater SHBG increases occurred with the 150 min/week prescription in non-obese women, which was unexpected, but this effect was diminished in the per-protocol sample (data not shown). Results stratified by time in zone suggested an enhanced dose effect on E2 when most of the prescribed exercise was done at high intensity. However, the dose effect seemed to be due to relatively small E2 changes in women who exercised for a moderate duration (135–150 min/week) at mainly high intensity (≥112 min/week) for reasons that are unclear. Perhaps exercise compensation was more common in this subgroup. With regard to estrone, the modest changes observed in BETA and the lack of dose dependency, as in the ALPHA trial (Friedenreich et al. 2010), overall do not support a dose–response relation between estrone and our exercise prescriptions. An important limitation of our trial was that the statistical power for assessing the efficacy of 300 min/week aerobic exercise was lower than planned because some women exercised below this level. Sensitivity analyses to account for non-adherence indeed revealed slightly stronger dose–response trends for total and free E2 changes (Tables 4 and 5) suggesting that significant dose effects might have been found if more women assigned to the high volume group had exercised >245 min/week. Still, 12-month E2 changes even at the highest levels of adherence were modest (<14%). Furthermore, we acknowledge the key limitations of our per-protocol analyses – namely, selection bias and lower statistical power. Finally, the generalizability of our results may be limited to healthy postmenopausal women with BMI 22–40 kg/m2, who are non-users of exogenous hormones and physically inactive but highly motivated to exercise.

To our knowledge, BETA is the largest dose–response exercise trial designed to inform postmenopausal breast cancer prevention. In previous dose–response RCTs, exercise prescriptions did not target primary cancer prevention, few breast cancer biomarkers were assessed, and only some (Asikainen et al. 2002, Asikainen et al. 2003, Morss et al. 2004, Dalleck et al. 2009) studied postmenopausal women exclusively. The dose–response to Exercise in Women trial (Morss et al. 2004, Church et al. 2009) was a large RCT statistically powered to compare exercise durations in over 450 postmenopausal women. However, lower volumes of exercise were prescribed than in BETA (50% VO2max for approximately 75, 140, and 190 min/week) and sex hormones were not assessed. BETA was a long-term intervention trial that was tightly controlled (Friedenreich et al. 2014) and study retention was exceptionally good with a 3.5% dropout rate overall. Furthermore, our extraction-based assays for quantifying estrone and E2 in serum were sensitive and specific (Endogenous Hormones and Breast Cancer Collaborative Group 2015).

In conclusion, our intention-to-treat analysis provided no evidence of a difference, with respect to endogenous estrogen or SHBG changes, in prescribing 300 vs 150 min/week of moderate-vigorous aerobic exercise to inactive postmenopausal women. For some individuals, dietary modification may be more feasible than increasing exercise volume for the purpose of lowering endogenous estrogen concentrations. For instance, one previous RCT in 439 overweight/obese postmenopausal women showed that free E2 concentrations were decreased by ∼5% on average in women prescribed 12 months of aerobic exercise, vs 26% in women prescribed exercise and a reduced-calorie diet (Campbell et al. 2012). Still, higher (vs lower) volumes of aerobic exercise offer important benefits for many other facets of postmenopausal health including physical fitness, cardiovascular and cognitive health, and overall survival (Church et al. 2007, Swift et al. 2012, Anderson et al. 2014). Furthermore, 300 min/week of aerobic exercise may be superior to 150 min/week for lowering breast cancer risk through other biologic pathways besides sex hormones, for example, insulin sensitivity and chronic low-grade inflammation (Rose & Vona-Davis 2014). Future analyses from BETA will address this question. The effects of exercise on myokines (Hojman et al. 2011), immune function, oxidative stress, telomere length and DNA methylation have been understudied in the context of breast cancer risk (Neilson et al. 2014) and could also be examined in future exercise trials.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

Research relating to this analysis was funded by a research grant from the Alberta Cancer Foundation (#24404). Dr C M Friedenreich holds a Health Senior Scholar Award from Alberta Innovates-Health Solutions and the Alberta Cancer Foundation Weekend to End Women's Cancers Breast Cancer Chair. Drs K S Courneya and Y Yasui are supported by the Canada Research Chairs Program. ClinicalTrials.gov Registration Number: NCT01435005.

Author contribution statement

Study design and funding: C M Friedenreich, K S Courneya, F Z Stanczyk, Y Yasui, A Duha. Study conduct: Friedenreich, Courneya, Stanczyk, Duha, MacLaughlin, Kallal, Forbes. Data management: C M Friedenreich, S MacLaughlin, C Kallal, Q Wang. Data analysis: Q Wang, H K Neilson, C M Friedenreich. Data interpretation: C M Friedenreich, K S Courneya, Y Yasui, H K Neilson, Q Wang, C Kallal, C C Forbes. Manuscript writing: H K Neilson, C M Friedenreich, K S Courneya. Manuscript review and approval: All authors

Acknowledgements

Calgary Study Coordinators were Krista Carlson, Sana Fakih, Megan Farris, Quinn Harris, Erica Roberts, and Kristen Simone. Edmonton Study Coordinators were Natalie Ilkiw, and Dr Amy Speed Andrews. Assistance with information sessions was provided in Calgary by Drs Brigid Lynch and Fabiola Aparicio-Ting. Calgary Exercise Trainers were Carrie Anderson, Alia Bharwani, Shannon Brown, Ashley Cuthbert, Sue Daniel, Julie Gowans, Margo Graham, Erin Korsbrek, Kathleen Kranenburg, Jessica Morrison, Jason Ng, Nicole Slot, Tania White, and Kaila Wright. Edmonton Exercise Trainers were Arne Anderson, Lisa Belanger, Jennifer Crawford, Cindy Forbes, Alyssa Hindle, Corey Kuzik, Erin McGowan, Mary Norris, Janel Park, Julianne Symons, Linda Trinh, Stephanie Voaklander and Lynne Wong. Study recruiters were Jennie Duke, Jasdeep Hayer, Trisha Kelly, Jasmine Lee, and Lilly Mah. Data entry was done by Sinead Boyle, Barbara Mercer, Carla Quesnel and Trish Kelly. Biospecimen support was provided by Catherine Munro. Data management, including database creation, questionnaire design, data integrity and quality control, was done by Dr Steven Szarka, Farit Vakhetov, Wendy Walroth and Rachel O'Reilly.

References

  • Ainsworth BE, Haskell WL, Herrmann SD, Meckes N, Bassett DR Jr, Tudor-Locke C, Greer JL, Vezina J, Whitt-Glover MC & Leon AS 2011 Compendium of physical activities: a second update of codes and MET values. Medicine and Science in Sports and Exercise 43 15751581. (doi:10.1249/MSS.0b013e31821ece12).

    • Search Google Scholar
    • Export Citation
  • American College of Sports Medicine 2000 ACSM's Guidelines for Exercise Testing and Prescription. Philadelphia, PA: Lippincott Williams & Wilkins

  • Anderson D, Seib C & Rasmussen L 2014 Can physical activity prevent physical and cognitive decline in postmenopausal women? A systematic review of the literature. Maturitas 79 1433. (doi:10.1016/j.maturitas.2014.06.010).

    • Search Google Scholar
    • Export Citation
  • Asikainen TM, Miilunpalo S, Oja P, Rinne M, Pasanen M, Uusi-Rasi K & Vuori I 2002 Randomised, controlled walking trials in postmenopausal women: the minimum dose to improve aerobic fitness? British Journal of Sports Medicine 36 189194. (doi:10.1136/bjsm.36.3.189).

    • Search Google Scholar
    • Export Citation
  • Asikainen TM, Miilunpalo S, Kukkonen-Harjula K, Nenonen A, Pasanen M, Rinne M, Uusi-Rasi K, Oja P & Vuori I 2003 Walking trials in postmenopausal women: effect of low doses of exercise and exercise fractionization on coronary risk factors. Scandinavian Journal of Medicine & Science in Sports 13 284292. (doi:10.1034/j.1600-0838.2003.00331.x).

    • Search Google Scholar
    • Export Citation
  • Borg G 1998 Borg's Perceived Exertion and Pain Scales. Champaign, IL, USA: Human Kinetics

  • Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, Mason C, Imayama I, Kong A & Xiao L et al. 2012 Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. Journal of Clinical Oncology 30 23142326. (doi:10.1200/JCO.2011.37.9792).

    • Search Google Scholar
    • Export Citation
  • Canadian Society for Exercise Physiology 2003 The Canadian Physical Activity, Fitness and Lifestyle Approach (CPAFLA): CSEP – Health and Fitness Program's Health-Related Appraisal and Counselling Strategy. Ottawa, ON, USA: Canadian Society for Exercise Physiology

  • Canadian Society for Exercise Physiology 2011 Canadian Physical Activity Guidelines for Adults – 18–64 years. Ottowa, ON, Canada: Canadian Society for Exercise Physiology. (available at: www.csep.ca/guidelines).

  • Church TS, Earnest CP, Skinner JS & Blair SN 2007 Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. Journal of the American Medical Association 297 20812091. (doi:10.1001/jama.297.19.2081).

    • Search Google Scholar
    • Export Citation
  • Church TS, Martin CK, Thompson AM, Earnest CP, Mikus CR & Blair SN 2009 Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women. PLoS ONE 4 e4515. (doi:10.1371/journal.pone.0004515).

    • Search Google Scholar
    • Export Citation
  • Copeland JL & Tremblay MS 2004 Effect of HRT on hormone responses to resistance exercise in post-menopausal women. Maturitas 48 360371. (doi:10.1016/j.maturitas.2003.09.025).

    • Search Google Scholar
    • Export Citation
  • Csizmadi I, Kahle L, Ullman R, Dawe U, Zimmerman T, Friedenreich CM, Bryant HE & Subar A 2007 Adaptation and evaluation of the National Cancer Institute's Dietary History Questionnaire and nutrient database for use in Canadian Populations. Public Health Nutrition 10 8896. (doi:10.1017/S1368980007184287).

    • Search Google Scholar
    • Export Citation
  • Dalleck LC, Allen BA, Hanson BA, Borresen EC, Erickson ME & De Lap SL 2009 Dose–response relationship between moderate-intensity exercise duration and coronary heart disease risk factors in postmenopausal women. Journal of Women's Health 18 105113. (doi:10.1089/jwh.2008.0790).

    • Search Google Scholar
    • Export Citation
  • Endogenous Hormones and Breast Cancer Collaborative Group 2015 Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies. Steroids 99 4955. (doi:10.1016/j.steroids.2014.09.001).

    • Search Google Scholar
    • Export Citation
  • Endogenous Hormones and Breast Cancer Collaborative Group XX, Key TJ, Appleby PN, Reeves GK, Roddam AW, Helzlsouer KJ, Alberg AJ, Rollison DE, Dorgan JF & Brinton LA 2011 Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. British Journal of Cancer 105 709722. (doi:10.1038/bjc.2011.254).

    • Search Google Scholar
    • Export Citation
  • Figueroa A, Going SB, Milliken LA, Blew RM, Sharp S, Teixeira PJ & Lohman TG 2003 Effects of exercise training and hormone replacement therapy on lean and fat mass in postmenopausal women. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 58 M266M270. (doi:10.1093/gerona/58.3.M266).

    • Search Google Scholar
    • Export Citation
  • Folkerd E & Dowsett M 2013 Sex hormones and breast cancer risk and prognosis. Breast 22 (Suppl 2) S38S43. (doi:10.1016/j.breast.2013.07.007).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Courneya KS, Neilson HK, Matthews CE, Willis G, Irwin M, Troiano R & Ballard-Barbash R 2006 Reliability and validity of the past year total physical activity questionnaire. American Journal of Epidemiology 163 959970. (doi:10.1093/aje/kwj112).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Woolcott CG, McTiernan A, Ballard-Barbash R, Brant RF, Stanczyk FZ, Terry T, Boyd NF, Yaffe MJ & Irwin ML et al. 2010 Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. Journal of Clinical Oncology 28 14581466. (doi:10.1200/JCO.2009.24.9557).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Neilson HK, Woolcott CG, Wang Q, Yasui Y, Brant RF, Stanczyk FZ, Campbell KL & Courneya KS 2011 Mediators and moderators of the effects of a year-long exercise intervention on endogenous sex hormones in postmenopausal women. Cancer Causes & Control 22 13651373. (doi:10.1007/s10552-011-9809-5).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, MacLaughlin S, Neilson HK, Stanczyk FZ, Yasui Y, Duha A, Lynch BM, Kallal C & Courneya KS 2014 Study design and methods for the breast cancer and exercise trial in Alberta (BETA). BMC Cancer 14 919. (doi:10.1186/1471-2407-14-919).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Neilson HK, O'Reilly R, Duha A, Yasui Y, Morielli AR, Adams SC & Courneya KS Effects of a high versus moderate volume of aerobic exercise on adiposity outcomes in postmenopausal women: a randomized clinical trial JAMA Oncology 2015 [in press] doi:10.1001/jamaoncol.2015.2239).

    • Search Google Scholar
    • Export Citation
  • Goto A, Chen BH, Song Y, Cauley J, Cummings SR, Farhat GN, Gunter M, Van Horn L, Howard BV & Jackson R et al. 2014 Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women. Clinical Chemistry 60 174185. (doi:10.1373/clinchem.2013.207217).

    • Search Google Scholar
    • Export Citation
  • Grubb RL III, Black A, Izmirlian G, Hickey TP, Pinsky PF, Mabie JE, Riley TL, Ragard LR, Prorok PC & Berg CD et al. 2009 Serum prostate-specific antigen hemodilution among obese men undergoing screening in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiology, Biomarkers & Prevention 18 748751. (doi:10.1158/1055-9965.EPI-08-0938).

    • Search Google Scholar
    • Export Citation
  • Hastert TA, Beresford SAA, Patterson RE, Kristal AR & White E 2013 Adherence to WCRF/AICR cancer prevention recommendations and risk of postmenopausal breast cancer. Cancer Epidemiology, Biomarkers & Prevention 22 14981508. (doi:10.1158/1055-9965.EPI-13-0210).

    • Search Google Scholar
    • Export Citation
  • Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L & Pedersen BK 2011 Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. American Journal of Physiology. Endocrinology and Metabolism 301 E504E510. (doi:10.1152/ajpendo.00520.2010).

    • Search Google Scholar
    • Export Citation
  • James RE, Lukanova A, Dossus L, Becker S, Rinaldi S, Tjonneland A, Olsen A, Overvad K, Mesrine S & Engel P et al. 2011 Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case–control study. Cancer Prevention Research 4 16261635. (doi:10.1158/1940-6207.CAPR-11-0090).

    • Search Google Scholar
    • Export Citation
  • Jones ME, Schoemaker M, Rae M, Folkerd EJ, Dowsett M, Ashworth A & Swerdlow AJ 2013 Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index. Journal of Clinical Endocrinology and Metabolism 98 29672974. (doi:10.1210/jc.2013-1588).

    • Search Google Scholar
    • Export Citation
  • Key T, Appleby P, Barnes I & Reeves G 2002 Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. Journal of the National Cancer Institute 94 606616. (doi:10.1093/jnci/94.8.606).

    • Search Google Scholar
    • Export Citation
  • Kim JW & Kim DY 2012 Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women. Metabolic Syndrome and Related Disorders 10 452457. (doi:10.1089/met.2012.0036).

    • Search Google Scholar
    • Export Citation
  • Kinoshita T, Honma S, Shibata Y, Yamashita K, Watanabe Y, Maekubo H, Okuyama M, Takashima A & Takeshita N 2014 An innovative LC-MS/MS-based method for determining CYP 17 and CYP 19 activity in the adipose tissue of pre- and postmenopausal and ovariectomized women using 13C-labeled steroid substrates. Journal of Clinical Endocrinology and Metabolism 99 13391347. (doi:10.1210/jc.2013-3715).

    • Search Google Scholar
    • Export Citation
  • Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K & Gansler T 2012 American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA: A Cancer Journal for Clinicians 62 3067. (doi:10.3322/caac.20140).

    • Search Google Scholar
    • Export Citation
  • Liedtke S, Schmidt ME, Vrieling A, Lukanova A, Becker S, Kaaks R, Zaineddin AK, Buck K, Benner A & Chang-Claude J et al. 2012 Postmenopausal sex hormones in relation to body fat distribution. Obesity 20 10881095. (doi:10.1038/oby.2011.383).

    • Search Google Scholar
    • Export Citation
  • McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irwin ML, Rajan KB, Sorensen B, Rudolph RE, Bowen D & Stanczyk FZ et al. 2004 Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Research 64 29232928. (doi:10.1158/0008-5472.CAN-03-3393).

    • Search Google Scholar
    • Export Citation
  • Monninkhof EM, Velthuis MJ, Peeters PH, Twisk JW & Schuit AJ 2009 Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial. Journal of Clinical Oncology 27 44924499. (doi:10.1200/JCO.2008.19.7459).

    • Search Google Scholar
    • Export Citation
  • Morss GM, Jordan AN, Skinner JS, Dunn AL, Church TS, Earnest CP, Kampert JB, Jurca R & Blair SN 2004 Dose response to exercise in women aged 45–75 yr (DREW): design and rationale. Medicine and Science in Sports and Exercise 36 336344. (doi:10.1249/01.MSS.0000113738.06267.E5).

    • Search Google Scholar
    • Export Citation
  • National Institutes of Health XX 1998 Executive summary: clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults – the evidence report. Obesity Research 6 (Suppl 2) 51S209S. (doi:10.1002/j.1550-8528.1998.tb00690.x).

    • Search Google Scholar
    • Export Citation
  • Neilson HK, Conroy SM & Friedenreich CM 2014 The influence of energetic factors on biomarkers of postmenopausal breast cancer risk. Current Nutrition Reports 3 2234. (doi:10.1007/s13668-013-0069-8).

    • Search Google Scholar
    • Export Citation
  • Orsatti FL, Nahas EAP, Maesta N, Nahas-Neto J & Burini RC 2008 Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women. Maturitas 59 394404. (doi:10.1016/j.maturitas.2008.04.002).

    • Search Google Scholar
    • Export Citation
  • Pearson TC, Guthrie DL, Simpson J, Chinn S, Barosi G, Ferrant A, Lewis SM & Najean Y 1995 Interpretation of measured red cell mass and plasma volume in adults: expert panel on radionuclides of the International Council for Standardization in Haematology. British Journal of Haematology 89 748756. (doi:10.1111/j.1365-2141.1995.tb08411.x).

    • Search Google Scholar
    • Export Citation
  • Pollock ML, Foster C, Schmidt D, Hellman C, Linnerud AC & Ward A 1982 Comparative analysis of physiologic responses to three different maximal graded exercise test protocols in healthy women. American Heart Journal 103 363373. (doi:10.1016/0002-8703(82)90275-7).

    • Search Google Scholar
    • Export Citation
  • Pugeat M, Crave JC, Elmidani M, Nicolas MH, Garoscio-Cholet M, Lejeune H, Dechaud H & Tourniaire J 1991 Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. Journal of Steroid Biochemistry and Molecular Biology 40 841849. (doi:10.1016/0960-0760(91)90310-2).

    • Search Google Scholar
    • Export Citation
  • R Core Team 2010 R: A Language and Environment for Statistical Computing. Version 2.11. Vienna: R Foundation for Statistical Computing

  • Rose DP & Vona-Davis L 2014 Biochemical and molecular mechanisms for the association between obesity, chronic Inflammation, and breast cancer. Biofactors 40 112. (doi:10.1002/biof.1109).

    • Search Google Scholar
    • Export Citation
  • Rosner B 2011 Hypothesis testing: two-sample inference. In Fundamentals of Biostatistics, 7th edn, Boston, MA, USA: Brooks/Cole

  • Rundle A 2005 Molecular epidemiology of physical activity and cancer. Cancer Epidemiology, Biomarkers & Prevention 14 227236. (doi:10.1158/1055-9965.EPI-04-0860).

    • Search Google Scholar
    • Export Citation
  • Stolzenberg-Solomon RZ, Falk RT, Stanczyk F, Hoover RN, Appel LJ, Ard JD, Batch BC, Coughlin J, Han X & Lien LF et al. 2012 Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African–American and non-African–American women. Breast Cancer Research 14 R141. (doi:10.1186/bcr3346).

    • Search Google Scholar
    • Export Citation
  • Suzuki R, Orsini N, Saji S, Key TJ & Wolk A 2009 Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status–a meta-analysis. International Journal of Cancer 124 698712. (doi:10.1002/ijc.23943).

    • Search Google Scholar
    • Export Citation
  • Swift DL, Earnest CP, Katzmarzyk PT, Rankinen T, Blair SN & Church TS 2012 The effect of different doses of aerobic exercise training on exercise blood pressure in overweight and obese postmenopausal women. Menopause 19 503509. (doi:10.1097/gme.0b013e318238ea66).

    • Search Google Scholar
    • Export Citation
  • Tworoger SS, Rosner BA, Willett WC & Hankinson SE 2011 The combined influence of multiple sex and growth hormones on risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Research 13 R99. (doi:10.1186/bcr3040).

    • Search Google Scholar
    • Export Citation
  • Tworoger SS, Zhang X, Eliassen AH, Qian J, Colditz GA, Willett WC, Rosner BA, Kraft P & Hankinson SE 2014 Inclusion of endogenous hormone levels in risk prediction models of postmenopausal breast cancer. Journal of Clinical Oncology 32 31113117. (doi:10.1200/JCO.2014.56.1068).

    • Search Google Scholar
    • Export Citation
  • Woolcott CG, Shvetsov YB, Stanczyk FZ, Wilkens LR, White KK, Caberto C, Henderson BE, Le Marchand L, Kolonel LN & Goodman MT 2010 Plasma sex hormone concentrations and breast cancer risk in an ethnically diverse population of postmenopausal women: the Multiethnic Cohort Study. Endocrine-Related Cancer 17 125134. (doi:10.1677/ERC-09-0211).

    • Search Google Scholar
    • Export Citation
  • World Cancer Research Fund/American Institute for Cancer Research 2007 Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington, DC: AICR

  • World Cancer Research Fund/American Institute for Cancer Research 2010 Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Breast Cancer. Washington, DC: AICR

  • World Health Organization 2011 Recommended population levels of physical activity for health. In Global recommendations on physical activity for health, pp 15–34. Geneva, Switzerland: World Health Organization. (available at: www.who.int/dietphysicalactivity/publications/9789241599979/en/).

  • Wu Y, Zhang D & Kang S 2013 Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Research and Treatment 137 869882. (doi:10.1007/s10549-012-2396-7).

    • Search Google Scholar
    • Export Citation
  • Yang HP, Black A, Falk RT, Brinton LA, Potischman N, Wentzensen N, Faupel-Badger JM & Sherman ME 2011 Association of serum sex steroid hormone hemodilution and body mass index among healthy postmenopausal women. Annals of Epidemiology 21 466471. (doi:10.1016/j.annepidem.2011.01.003).

    • Search Google Scholar
    • Export Citation
  • Yoo EJ, Jun TW & Hawkins S 2010 The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women. Research in Sports Medicine 18 236250. (doi:10.1080/15438627.2010.510098).

    • Search Google Scholar
    • Export Citation
  • Zhang X, Tworoger SS, Eliassen AH & Hankinson SE 2013 Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Research and Treatment 137 883892. (doi:10.1007/s10549-012-2391-z).

    • Search Google Scholar
    • Export Citation

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 2086 322 33
PDF Downloads 776 285 22
  • View in gallery

    CONSORT diagram: Flow of participants through the BETA trial, Alberta, Canada, 2010–2013.

  • Ainsworth BE, Haskell WL, Herrmann SD, Meckes N, Bassett DR Jr, Tudor-Locke C, Greer JL, Vezina J, Whitt-Glover MC & Leon AS 2011 Compendium of physical activities: a second update of codes and MET values. Medicine and Science in Sports and Exercise 43 15751581. (doi:10.1249/MSS.0b013e31821ece12).

    • Search Google Scholar
    • Export Citation
  • American College of Sports Medicine 2000 ACSM's Guidelines for Exercise Testing and Prescription. Philadelphia, PA: Lippincott Williams & Wilkins

  • Anderson D, Seib C & Rasmussen L 2014 Can physical activity prevent physical and cognitive decline in postmenopausal women? A systematic review of the literature. Maturitas 79 1433. (doi:10.1016/j.maturitas.2014.06.010).

    • Search Google Scholar
    • Export Citation
  • Asikainen TM, Miilunpalo S, Oja P, Rinne M, Pasanen M, Uusi-Rasi K & Vuori I 2002 Randomised, controlled walking trials in postmenopausal women: the minimum dose to improve aerobic fitness? British Journal of Sports Medicine 36 189194. (doi:10.1136/bjsm.36.3.189).

    • Search Google Scholar
    • Export Citation
  • Asikainen TM, Miilunpalo S, Kukkonen-Harjula K, Nenonen A, Pasanen M, Rinne M, Uusi-Rasi K, Oja P & Vuori I 2003 Walking trials in postmenopausal women: effect of low doses of exercise and exercise fractionization on coronary risk factors. Scandinavian Journal of Medicine & Science in Sports 13 284292. (doi:10.1034/j.1600-0838.2003.00331.x).

    • Search Google Scholar
    • Export Citation
  • Borg G 1998 Borg's Perceived Exertion and Pain Scales. Champaign, IL, USA: Human Kinetics

  • Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, Mason C, Imayama I, Kong A & Xiao L et al. 2012 Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. Journal of Clinical Oncology 30 23142326. (doi:10.1200/JCO.2011.37.9792).

    • Search Google Scholar
    • Export Citation
  • Canadian Society for Exercise Physiology 2003 The Canadian Physical Activity, Fitness and Lifestyle Approach (CPAFLA): CSEP – Health and Fitness Program's Health-Related Appraisal and Counselling Strategy. Ottawa, ON, USA: Canadian Society for Exercise Physiology

  • Canadian Society for Exercise Physiology 2011 Canadian Physical Activity Guidelines for Adults – 18–64 years. Ottowa, ON, Canada: Canadian Society for Exercise Physiology. (available at: www.csep.ca/guidelines).

  • Church TS, Earnest CP, Skinner JS & Blair SN 2007 Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. Journal of the American Medical Association 297 20812091. (doi:10.1001/jama.297.19.2081).

    • Search Google Scholar
    • Export Citation
  • Church TS, Martin CK, Thompson AM, Earnest CP, Mikus CR & Blair SN 2009 Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women. PLoS ONE 4 e4515. (doi:10.1371/journal.pone.0004515).

    • Search Google Scholar
    • Export Citation
  • Copeland JL & Tremblay MS 2004 Effect of HRT on hormone responses to resistance exercise in post-menopausal women. Maturitas 48 360371. (doi:10.1016/j.maturitas.2003.09.025).

    • Search Google Scholar
    • Export Citation
  • Csizmadi I, Kahle L, Ullman R, Dawe U, Zimmerman T, Friedenreich CM, Bryant HE & Subar A 2007 Adaptation and evaluation of the National Cancer Institute's Dietary History Questionnaire and nutrient database for use in Canadian Populations. Public Health Nutrition 10 8896. (doi:10.1017/S1368980007184287).

    • Search Google Scholar
    • Export Citation
  • Dalleck LC, Allen BA, Hanson BA, Borresen EC, Erickson ME & De Lap SL 2009 Dose–response relationship between moderate-intensity exercise duration and coronary heart disease risk factors in postmenopausal women. Journal of Women's Health 18 105113. (doi:10.1089/jwh.2008.0790).

    • Search Google Scholar
    • Export Citation
  • Endogenous Hormones and Breast Cancer Collaborative Group 2015 Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies. Steroids 99 4955. (doi:10.1016/j.steroids.2014.09.001).

    • Search Google Scholar
    • Export Citation
  • Endogenous Hormones and Breast Cancer Collaborative Group XX, Key TJ, Appleby PN, Reeves GK, Roddam AW, Helzlsouer KJ, Alberg AJ, Rollison DE, Dorgan JF & Brinton LA 2011 Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. British Journal of Cancer 105 709722. (doi:10.1038/bjc.2011.254).

    • Search Google Scholar
    • Export Citation
  • Figueroa A, Going SB, Milliken LA, Blew RM, Sharp S, Teixeira PJ & Lohman TG 2003 Effects of exercise training and hormone replacement therapy on lean and fat mass in postmenopausal women. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 58 M266M270. (doi:10.1093/gerona/58.3.M266).

    • Search Google Scholar
    • Export Citation
  • Folkerd E & Dowsett M 2013 Sex hormones and breast cancer risk and prognosis. Breast 22 (Suppl 2) S38S43. (doi:10.1016/j.breast.2013.07.007).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Courneya KS, Neilson HK, Matthews CE, Willis G, Irwin M, Troiano R & Ballard-Barbash R 2006 Reliability and validity of the past year total physical activity questionnaire. American Journal of Epidemiology 163 959970. (doi:10.1093/aje/kwj112).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Woolcott CG, McTiernan A, Ballard-Barbash R, Brant RF, Stanczyk FZ, Terry T, Boyd NF, Yaffe MJ & Irwin ML et al. 2010 Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. Journal of Clinical Oncology 28 14581466. (doi:10.1200/JCO.2009.24.9557).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Neilson HK, Woolcott CG, Wang Q, Yasui Y, Brant RF, Stanczyk FZ, Campbell KL & Courneya KS 2011 Mediators and moderators of the effects of a year-long exercise intervention on endogenous sex hormones in postmenopausal women. Cancer Causes & Control 22 13651373. (doi:10.1007/s10552-011-9809-5).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, MacLaughlin S, Neilson HK, Stanczyk FZ, Yasui Y, Duha A, Lynch BM, Kallal C & Courneya KS 2014 Study design and methods for the breast cancer and exercise trial in Alberta (BETA). BMC Cancer 14 919. (doi:10.1186/1471-2407-14-919).

    • Search Google Scholar
    • Export Citation
  • Friedenreich CM, Neilson HK, O'Reilly R, Duha A, Yasui Y, Morielli AR, Adams SC & Courneya KS Effects of a high versus moderate volume of aerobic exercise on adiposity outcomes in postmenopausal women: a randomized clinical trial JAMA Oncology 2015 [in press] doi:10.1001/jamaoncol.2015.2239).

    • Search Google Scholar
    • Export Citation
  • Goto A, Chen BH, Song Y, Cauley J, Cummings SR, Farhat GN, Gunter M, Van Horn L, Howard BV & Jackson R et al. 2014 Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women. Clinical Chemistry 60 174185. (doi:10.1373/clinchem.2013.207217).

    • Search Google Scholar
    • Export Citation
  • Grubb RL III, Black A, Izmirlian G, Hickey TP, Pinsky PF, Mabie JE, Riley TL, Ragard LR, Prorok PC & Berg CD et al. 2009 Serum prostate-specific antigen hemodilution among obese men undergoing screening in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiology, Biomarkers & Prevention 18 748751. (doi:10.1158/1055-9965.EPI-08-0938).

    • Search Google Scholar
    • Export Citation
  • Hastert TA, Beresford SAA, Patterson RE, Kristal AR & White E 2013 Adherence to WCRF/AICR cancer prevention recommendations and risk of postmenopausal breast cancer. Cancer Epidemiology, Biomarkers & Prevention 22 14981508. (doi:10.1158/1055-9965.EPI-13-0210).

    • Search Google Scholar
    • Export Citation
  • Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L & Pedersen BK 2011 Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. American Journal of Physiology. Endocrinology and Metabolism 301 E504E510. (doi:10.1152/ajpendo.00520.2010).

    • Search Google Scholar
    • Export Citation
  • James RE, Lukanova A, Dossus L, Becker S, Rinaldi S, Tjonneland A, Olsen A, Overvad K, Mesrine S & Engel P et al. 2011 Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case–control study. Cancer Prevention Research 4 16261635. (doi:10.1158/1940-6207.CAPR-11-0090).

    • Search Google Scholar
    • Export Citation
  • Jones ME, Schoemaker M, Rae M, Folkerd EJ, Dowsett M, Ashworth A & Swerdlow AJ 2013 Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index. Journal of Clinical Endocrinology and Metabolism 98 29672974. (doi:10.1210/jc.2013-1588).

    • Search Google Scholar
    • Export Citation
  • Key T, Appleby P, Barnes I & Reeves G 2002 Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. Journal of the National Cancer Institute 94 606616. (doi:10.1093/jnci/94.8.606).

    • Search Google Scholar
    • Export Citation
  • Kim JW & Kim DY 2012 Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women. Metabolic Syndrome and Related Disorders 10 452457. (doi:10.1089/met.2012.0036).

    • Search Google Scholar
    • Export Citation
  • Kinoshita T, Honma S, Shibata Y, Yamashita K, Watanabe Y, Maekubo H, Okuyama M, Takashima A & Takeshita N 2014 An innovative LC-MS/MS-based method for determining CYP 17 and CYP 19 activity in the adipose tissue of pre- and postmenopausal and ovariectomized women using 13C-labeled steroid substrates. Journal of Clinical Endocrinology and Metabolism 99 13391347. (doi:10.1210/jc.2013-3715).

    • Search Google Scholar
    • Export Citation
  • Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K & Gansler T 2012 American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA: A Cancer Journal for Clinicians 62 3067. (doi:10.3322/caac.20140).

    • Search Google Scholar
    • Export Citation
  • Liedtke S, Schmidt ME, Vrieling A, Lukanova A, Becker S, Kaaks R, Zaineddin AK, Buck K, Benner A & Chang-Claude J et al. 2012 Postmenopausal sex hormones in relation to body fat distribution. Obesity 20 10881095. (doi:10.1038/oby.2011.383).

    • Search Google Scholar
    • Export Citation
  • McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irwin ML, Rajan KB, Sorensen B, Rudolph RE, Bowen D & Stanczyk FZ et al. 2004 Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Research 64 29232928. (doi:10.1158/0008-5472.CAN-03-3393).

    • Search Google Scholar
    • Export Citation
  • Monninkhof EM, Velthuis MJ, Peeters PH, Twisk JW & Schuit AJ 2009 Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial. Journal of Clinical Oncology 27 44924499. (doi:10.1200/JCO.2008.19.7459).

    • Search Google Scholar
    • Export Citation
  • Morss GM, Jordan AN, Skinner JS, Dunn AL, Church TS, Earnest CP, Kampert JB, Jurca R & Blair SN 2004 Dose response to exercise in women aged 45–75 yr (DREW): design and rationale. Medicine and Science in Sports and Exercise 36 336344. (doi:10.1249/01.MSS.0000113738.06267.E5).

    • Search Google Scholar
    • Export Citation
  • National Institutes of Health XX 1998 Executive summary: clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults – the evidence report. Obesity Research 6 (Suppl 2) 51S209S. (doi:10.1002/j.1550-8528.1998.tb00690.x).

    • Search Google Scholar
    • Export Citation
  • Neilson HK, Conroy SM & Friedenreich CM 2014 The influence of energetic factors on biomarkers of postmenopausal breast cancer risk. Current Nutrition Reports 3 2234. (doi:10.1007/s13668-013-0069-8).

    • Search Google Scholar
    • Export Citation
  • Orsatti FL, Nahas EAP, Maesta N, Nahas-Neto J & Burini RC 2008 Plasma hormones, muscle mass and strength in resistance-trained postmenopausal women. Maturitas 59 394404. (doi:10.1016/j.maturitas.2008.04.002).

    • Search Google Scholar
    • Export Citation
  • Pearson TC, Guthrie DL, Simpson J, Chinn S, Barosi G, Ferrant A, Lewis SM & Najean Y 1995 Interpretation of measured red cell mass and plasma volume in adults: expert panel on radionuclides of the International Council for Standardization in Haematology. British Journal of Haematology 89 748756. (doi:10.1111/j.1365-2141.1995.tb08411.x).

    • Search Google Scholar
    • Export Citation
  • Pollock ML, Foster C, Schmidt D, Hellman C, Linnerud AC & Ward A 1982 Comparative analysis of physiologic responses to three different maximal graded exercise test protocols in healthy women. American Heart Journal 103 363373. (doi:10.1016/0002-8703(82)90275-7).

    • Search Google Scholar
    • Export Citation
  • Pugeat M, Crave JC, Elmidani M, Nicolas MH, Garoscio-Cholet M, Lejeune H, Dechaud H & Tourniaire J 1991 Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. Journal of Steroid Biochemistry and Molecular Biology 40 841849. (doi:10.1016/0960-0760(91)90310-2).

    • Search Google Scholar
    • Export Citation
  • R Core Team 2010 R: A Language and Environment for Statistical Computing. Version 2.11. Vienna: R Foundation for Statistical Computing

  • Rose DP & Vona-Davis L 2014 Biochemical and molecular mechanisms for the association between obesity, chronic Inflammation, and breast cancer. Biofactors 40 112. (doi:10.1002/biof.1109).

    • Search Google Scholar
    • Export Citation
  • Rosner B 2011 Hypothesis testing: two-sample inference. In Fundamentals of Biostatistics, 7th edn, Boston, MA, USA: Brooks/Cole

  • Rundle A 2005 Molecular epidemiology of physical activity and cancer. Cancer Epidemiology, Biomarkers & Prevention 14 227236. (doi:10.1158/1055-9965.EPI-04-0860).

    • Search Google Scholar
    • Export Citation
  • Stolzenberg-Solomon RZ, Falk RT, Stanczyk F, Hoover RN, Appel LJ, Ard JD, Batch BC, Coughlin J, Han X & Lien LF et al. 2012 Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African–American and non-African–American women. Breast Cancer Research 14 R141. (doi:10.1186/bcr3346).

    • Search Google Scholar
    • Export Citation
  • Suzuki R, Orsini N, Saji S, Key TJ & Wolk A 2009 Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status–a meta-analysis. International Journal of Cancer 124 698712. (doi:10.1002/ijc.23943).

    • Search Google Scholar
    • Export Citation
  • Swift DL, Earnest CP, Katzmarzyk PT, Rankinen T, Blair SN & Church TS 2012 The effect of different doses of aerobic exercise training on exercise blood pressure in overweight and obese postmenopausal women. Menopause 19 503509. (doi:10.1097/gme.0b013e318238ea66).

    • Search Google Scholar
    • Export Citation
  • Tworoger SS, Rosner BA, Willett WC & Hankinson SE 2011 The combined influence of multiple sex and growth hormones on risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Research 13 R99. (doi:10.1186/bcr3040).

    • Search Google Scholar
    • Export Citation
  • Tworoger SS, Zhang X, Eliassen AH, Qian J, Colditz GA, Willett WC, Rosner BA, Kraft P & Hankinson SE 2014 Inclusion of endogenous hormone levels in risk prediction models of postmenopausal breast cancer. Journal of Clinical Oncology 32 31113117. (doi:10.1200/JCO.2014.56.1068).

    • Search Google Scholar
    • Export Citation
  • Woolcott CG, Shvetsov YB, Stanczyk FZ, Wilkens LR, White KK, Caberto C, Henderson BE, Le Marchand L, Kolonel LN & Goodman MT 2010 Plasma sex hormone concentrations and breast cancer risk in an ethnically diverse population of postmenopausal women: the Multiethnic Cohort Study. Endocrine-Related Cancer 17 125134. (doi:10.1677/ERC-09-0211).

    • Search Google Scholar
    • Export Citation
  • World Cancer Research Fund/American Institute for Cancer Research 2007 Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington, DC: AICR

  • World Cancer Research Fund/American Institute for Cancer Research 2010 Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Breast Cancer. Washington, DC: AICR

  • World Health Organization 2011 Recommended population levels of physical activity for health. In Global recommendations on physical activity for health, pp 15–34. Geneva, Switzerland: World Health Organization. (available at: www.who.int/dietphysicalactivity/publications/9789241599979/en/).

  • Wu Y, Zhang D & Kang S 2013 Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Research and Treatment 137 869882. (doi:10.1007/s10549-012-2396-7).

    • Search Google Scholar
    • Export Citation
  • Yang HP, Black A, Falk RT, Brinton LA, Potischman N, Wentzensen N, Faupel-Badger JM & Sherman ME 2011 Association of serum sex steroid hormone hemodilution and body mass index among healthy postmenopausal women. Annals of Epidemiology 21 466471. (doi:10.1016/j.annepidem.2011.01.003).

    • Search Google Scholar
    • Export Citation
  • Yoo EJ, Jun TW & Hawkins S 2010 The effects of a walking exercise program on fall-related fitness, bone metabolism, and fall-related psychological factors in elderly women. Research in Sports Medicine 18 236250. (doi:10.1080/15438627.2010.510098).

    • Search Google Scholar
    • Export Citation
  • Zhang X, Tworoger SS, Eliassen AH & Hankinson SE 2013 Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Research and Treatment 137 883892. (doi:10.1007/s10549-012-2391-z).

    • Search Google Scholar
    • Export Citation