Document Detail

Mediators and moderators of the effects of a year-long exercise intervention on endogenous sex hormones in postmenopausal women.
Jump to Full Text
MedLine Citation:
PMID:  21732049     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To identify factors that mediate or moderate the effects of exercise on postmenopausal sex hormone concentrations.
METHODS: Postmenopausal women were randomized to 12 months of aerobic exercise for 200 min/week (n = 160) or to a control group (n = 160). Intention-to-treat analyses were performed using general linear models with sex hormone concentrations at 6 and 12 months as the outcome. Mediation by adiposity and insulin was investigated by examining changes in effect estimates after adjustment for changes in these factors over 12 months. Moderation was studied as the interaction between group assignment and eight baseline characteristics.
RESULTS: Intervention effects on sex hormone-binding globulin (SHBG) and estradiol changes were attenuated with adjustment for change in overall body fat, while there was less attenuation adjusting for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Significant interactions were identified between treatment and physical fitness (for SHBG and testosterone) and age (for testosterone), implying subgroup differences in intervention effect.
CONCLUSIONS: Our data suggest that overall fat loss partially mediated exercise-induced changes in estradiol and SHBG concentrations. No previous RCT in postmenopausal women has studied moderators of exercise-induced sex hormone changes; therefore, future studies are needed to corroborate our results.
Authors:
Christine M Friedenreich; Heather K Neilson; Christy G Woolcott; Qinggang Wang; Yutaka Yasui; Rollin F Brant; Frank Z Stanczyk; Kristin L Campbell; Kerry S Courneya
Related Documents :
23326709 - Marathon runner with acute hyponatremia: a neurological disorder.
22576339 - Aerobic exercise is promoted when individual performance affects the group: a test of t...
10749329 - Electrophysiological and mechanical activity of the upper gastrointestinal tract after ...
3678179 - Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, po...
12405699 - Oral l-carnitine combined with training promotes changes in skeletal muscle.
11843129 - Use of an extracorporeal circuit to evaluate effects of intraluminal distention and dec...
7476059 - Effects of exercise training on endothelium-dependent peripheral vascular responsiveness.
18715629 - Biomonitoring of genotoxicity using micronuclei assay in native population of astyanax ...
12381419 - Nitric oxide released from inos in polymorphonuclear leukocytes makes them deformable i...
Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2011-07-06
Journal Detail:
Title:  Cancer causes & control : CCC     Volume:  22     ISSN:  1573-7225     ISO Abbreviation:  Cancer Causes Control     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-20     Completed Date:  2012-04-04     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  9100846     Medline TA:  Cancer Causes Control     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1365-73     Citation Subset:  IM    
Affiliation:
Department of Population Health Research, Alberta Health Services-Cancer Care, Calgary, AB, T2N 4N2, Canada, christine.friedenreich@albertahealthservices.ca
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adipose Tissue / metabolism
Adiposity / physiology
Breast Neoplasms / blood,  metabolism,  prevention & control
Estradiol / blood*
Exercise / physiology*
Female
Gonadal Steroid Hormones / blood*
Humans
Insulin / blood
Intention to Treat Analysis / methods
Intra-Abdominal Fat / metabolism
Middle Aged
Postmenopause / blood*
Risk Factors
Sex Hormone-Binding Globulin / metabolism*
Testosterone / blood
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Gonadal Steroid Hormones; 0/Insulin; 0/Sex Hormone-Binding Globulin; 50-28-2/Estradiol; 58-22-0/Testosterone
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Cancer Causes Control
ISSN: 0957-5243
ISSN: 1573-7225
Publisher: Springer Netherlands, Dordrecht
Article Information
Download PDF
© The Author(s) 2011
Received Day: 16 Month: 3 Year: 2011
Accepted Day: 21 Month: 6 Year: 2011
Electronic publication date: Day: 6 Month: 7 Year: 2011
pmc-release publication date: Day: 6 Month: 7 Year: 2011
Print publication date: Month: 10 Year: 2011
Volume: 22 Issue: 10
First Page: 1365 Last Page: 1373
ID: 3176403
PubMed Id: 21732049
Publisher Id: 9809
DOI: 10.1007/s10552-011-9809-5

Mediators and moderators of the effects of a year-long exercise intervention on endogenous sex hormones in postmenopausal women
Christine M. Friedenreich1 Address: 403-521-3841 403-270-8003 christine.friedenreich@albertahealthservices.ca
Heather K. Neilson1
Christy G. Woolcott2
Qinggang Wang1
Yutaka Yasui3
Rollin F. Brant4
Frank Z. Stanczyk5
Kristin L. Campbell6
Kerry S. Courneya7
1Department of Population Health Research, Alberta Health Services–Cancer Care, Calgary, AB T2N 4N2 Canada
2Departments of Obstetrics and Gynaecology and Pediatrics, Dalhousie University, Halifax, NS Canada
3Department of Public Health Sciences, University of Alberta, Edmonton, AB Canada
4Department of Statistics, University of British Columbia, Vancouver, BC Canada
5Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA USA
6Department of Physical Therapy, University of British Columbia, Vancouver, BC Canada
7Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB Canada

Introduction

A wealth of epidemiologic evidence supports a preventive role for physical activity in postmenopausal breast cancer etiology, but the biologic changes mediating this association remain poorly understood [1, 2]. Two plausible mechanisms are a decrease in sex hormone concentrations and an increase in sex hormone–binding globulin (SHBG) concentrations, which are convincingly associated with postmenopausal breast cancer risk [3]. As adipose tissue is the main source of sex hormones in postmenopausal women, exercise-induced fat loss could drive changes in their levels [4]. Exercise-induced reductions in insulin could increase SHBG synthesis in the liver [5].

It is also unclear whether any factors moderate the association between physical activity and postmenopausal breast cancer risk. Although the epidemiologic evidence suggests that the relationship between physical activity and reduced postmenopausal breast cancer risk is probable [1, 2], there is variability across studies in the magnitude of the association, possibly attributable to subgroup differences in the study populations defined by factors such as age and BMI [1]. These factors, and others, may also modify the effects of physical activity on sex hormone or SHBG levels, perhaps because they relate to baseline levels of sex hormones and SHBG (high baseline levels may result in a ceiling effect whereby exercise will not result in further increase; low baseline levels may result in a floor effect whereby exercise will not result in further decrease) or because they relate to exercise adherence.

The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial was a randomized controlled trial (RCT) designed to determine the effects of a 12-month aerobic exercise intervention on proposed biomarkers of postmenopausal breast cancer risk. We previously reported that, relative to controls, postmenopausal women assigned to the intervention experienced significantly greater decreases in circulating total and free estradiol [6], circulating insulin [7], and total and abdominal fat [8] and significantly greater increases in SHBG levels [6]. Because clarifying the biologic mechanisms through which exercise induces sex hormone and SHBG changes and distinguishing subgroups of women in whom exercise may have a stronger effect on sex hormone and SHBG changes could help inform public health recommendations for lowering postmenopausal breast cancer risk, we present here a secondary analysis of ALPHA Trial data using analytic techniques described by Kraemer et al. [9] and Mackinnon and Fairchild [10] to (1) explore adiposity and insulin changes as potential mediators of the exercise-induced estradiol and SHBG changes we observed and (2) examine baseline characteristics as potential moderators of the intervention effect on changes in estradiol, estrone, testosterone, and SHBG, which are all convincingly associated with postmenopausal breast cancer risk [3].


Materials and methods
Study population

The ALPHA Trial study population and recruitment details have been described previously [6, 8]. Inactive women (<90 min/week recreational activity over the past year or, if between 90 and 120 min/week of physical activity had a VO2max < 34.5 mL/kg/min), aged 50–74 years, postmenopausal for at least 24 months, body mass index (BMI) 22–40 kg/m2, with no major co-morbidities or previous cancer diagnosis besides non-melanotic skin cancer, were recruited from the general population in Calgary and Edmonton, Alberta, Canada. Eligibility criteria also included the following: English-speaking, acceptable heart and lung function as assessed by a baseline fitness test, able to undertake unrestricted physical activity as assessed by their physician [11], normal levels of fasting lipids, glucose, thyroid-stimulating hormone and alanine aminotransferase, breast tissue density above a zero density level, non-diabetic, non-smoker, alcohol intake <14 drinks/week, no medications or exogenous hormones that might influence estrogen metabolism and not currently or planning to undertake a weight loss program or planning any extended absences in the 18 months subsequent to enrollment.

Intervention

The study participants were randomly allocated either to a year-long, moderate-to-vigorous-intensity, aerobic exercise intervention (n = 160) or to a control group (n = 160) assigned to no exercise. Details of randomization have been described previously [6]. The exercise intervention was individually prescribed program of at least 45 min of any type of aerobic exercise done 5 days per week for 12 months at 70–80% heart rate reserve. At least three sessions per week were supervised by exercise trainers at our fitness centers, and the rest were home-based. The frequency, duration, and intensity were gradually increased during the first 3 months of the intervention from 3 weekly sessions of 15- to 20-min duration at an intensity of 50–60% heart rate reserve to the final prescription achieved in week 12. Women in the control group were asked to maintain their regular inactive lifestyle. No changes to usual dietary intake were to be made in either group. Ethics approval was obtained from the Alberta Cancer Board and Universities of Calgary and Alberta, and all participants provided written informed consent.

Measurements

Baseline data on demographics, medical and medication history, self-rated health, and past year physical activity [12] were obtained by a self-administered questionnaire. Anthropometric measurements were taken in duplicate; if the two measurements were discrepant (i.e., not identical), a third measurement was taken and the average of the two closest was used in the analyses. Weight and height measurements were taken using a balance beam scale and a stadiometer. Body mass index was calculated as weight/height2 (kg/m2). At baseline and 12 months, total body fat and body fat percentage were measured using whole-body dual X-ray absorptiometry scans. In Calgary, scans were done on a Hologic QDR 4500 W® scanner in whole-body mode and analyzed with software version 11.2.1 (Hologic®, Inc., Bedford, MA, USA). In Edmonton, scans were done on a Lunar Prodigy® scanner in either standard mode or thick mode and analyzed with enCORE Software 6.70.01 before November 2004 and 8.60 after November 2004 (Lunar® General Electric Medical Systems, Madison, WI, USA). Percent body fat was calculated as 100% × {fat mass/(fat mass + lean mass)}. Intra-abdominal fat was measured with a single computed tomography slice at the umbilicus. In Calgary, scans were done using a Marconi PQ5000 VisionMaster/Picker, and in Edmonton, using a Phillips/Marconi MX8000 multislice scanner. The study radiologist used an image analysis software program (Phillips Medical Systems PQ5000) to identify and demarcate the thresholds between the subcutaneous and intra-abdominal area. Physical fitness was assessed at baseline and 12 months using a modified Balke treadmill protocol to estimate maximum oxygen consumption (VO2max) from submaximal exercise intensities. Oxygen consumption at the age-predicted maximum heart rate was estimated by extrapolating from the two last completed stages using the American College of Sports Medicine metabolic equations for estimating oxygen consumption at the workload of each stage [13].

Blood was collected after a minimum 10-h fast at baseline (60 mL), 6 and 12 months (40 mL), and medications taken in the past 24 h were recorded. Participants were asked not to exercise for 24 h pre-blood draw. All blood samples were collected, processed, and stored within 12 h of collection and then shipped and stored in −86°C freezers until time of assay. Analyses were conducted by the Reproductive Endocrine Research Laboratory at the University of Southern California, a laboratory with well-established protocols and quality control procedures. Serum estradiol and testosterone levels were quantified by radioimmunoassay after organic solvent extraction and Celite column partition chromatography [1416]. Chromatographic separation of the steroids was achieved by using different concentrations of toluene in iso-octane and ethyl acetate in iso-octane. Sex hormone–binding globulin (SHBG) and insulin were quantified via chemiluminescent immunometric assay using the Immulite Analyzer (Siemens Healthcare Diagnostics, Deerfield, IL). The SHBG concentration and an assumed albumin concentration of 43 g/L were then utilized in a validated algorithm with total estradiol to calculate free estradiol [17].

Hypothesized mediators and moderators

Our hypothesized mediators were body fat change (for sex hormones and SHBG) and circulating insulin change (for SHBG). These hypotheses were supported by our earlier review of the scientific literature on proposed biologic mechanisms relating physical activity to postmenopausal breast cancer risk [4]. Moreover, the proposed mediators, by definition [9], were associated with our exercise intervention; relative to controls, the exercise group in the ALPHA Trial experienced significantly greater decreases in total body fat, intra-abdominal fat area [8], and circulating insulin levels [7] over 12 months.

Potential moderators were baseline characteristics for ALPHA Trial participants that were selected for their hypothetical relations either to exercise adherence during the trial (e.g., baseline fitness level, age, years postmenopause, self-rated health, previous recreational activity, baseline BMI) or to changes in sex hormone levels (e.g., circulating levels of sex hormones at baseline, previous HRT use, baseline BMI). We hypothesized that women who exercised more might experience greater changes in sex hormone levels and that women with higher sex hormone levels or lower SHBG levels at baseline might experience greater changes as a result of the exercise intervention.

Statistical analyses

The analyses included participants with complete data and were based on assigned groups at randomization regardless of adherence. Hormone levels were log-transformed to achieve an approximate symmetric distribution. Intervention effects were evaluated with general linear models considering the repeated measures of sex hormone concentrations at 6 and 12 months. The model took the following form: Yij = β0 + β1Xi + γZij + εij, where, for the ith subject, Yij is a log-transformed outcome measure at jth time (j = 1 for 6 months, j = 2 for 12 months), Xi is an indicator variable for the exercise intervention arm (0 for control, 1 for exercise intervention), Zij is a vector of adjustment variables, and (εi1, εi2) is a correlated error vector following a bivariate Gaussian distribution with mean 0. Of the parameters β0, β1, and γ (associated with the intercept, exercise intervention, and adjustment variables, respectively), β1 is the target parameter, representing the adjusted difference in the mean log outcome between the exercise intervention group and the control group over the two follow-up time points, adjusting for Z. We refer to the exponential of β1 as the treatment effect ratio (TER), as it is a ratio of the adjusted geometric means of the outcome for the exercise intervention group over the control group. In this paper, we also refer to the TER as the ‘intervention effect’.

Our assessment of mediation was based on findings from the general linear model with both the intervention assignment and changes in the hypothesized mediators predicting changes in sex hormone or SHBG levels. Mediation by adiposity and insulin levels was investigated in two ways. Primarily, mediation was investigated by examining the change in the TER pre- versus postadjustment for changes in the hypothesized mediators at 6 and 12 months from baseline. If the adjustment attenuated TER, then we considered this finding to be suggestive of mediation [10]. Secondarily, the main effect of each potential mediator on sex hormone or SHBG changes was also evaluated in these models, adjusting for the intervention assignment. Kraemer et al. [9] explain that a mediator must measure a change occurring during treatment (e.g., changes in body fat and insulin levels occurred during the 12-month intervention period [7, 8]), must correlate with treatment assignment (e.g., we observed significantly greater changes in body fat and insulin levels in the exercise group than in controls [7, 8]), and must have either a main or interactive effect on the outcome. This secondary analysis is informative because it is these conditions under which our main analysis would suggest mediation.

Moderation was investigated by determining the statistical significance of the interaction term between the intervention assignment and each hypothesized moderator (described above), adjusting for the baseline outcome (e.g., baseline estradiol level), the intervention group assignment, time, and the hypothesized moderator (e.g., baseline age) [9]. All baseline characteristics were treated as continuous variables in these analyses with the exception of HRT use, which was dichotomized. To help explain our findings from these analyses, intervention effects were also estimated within subgroups of these characteristics. We reported intervention effects within all subgroups regardless of the statistical significance of the interaction term in general linear models. Subgroups were created by dichotomizing each variable at the median with the exception of self-rated health, which was measured by questionnaire using the SF-36 scale [18] (range, 0–100): ‘low’ was defined as a score <82 and ≥82 was considered ‘high’. All statistical tests were two-sided with a significance level set at 0.05. Statistical analyses were performed using SAS software (version 9.1; SAS Institute, Inc., Cary NC).


Results

The flow of participants through the trial has been reported elsewhere [6]. Briefly, we assessed 3,454 women for eligibility and 320 women were randomized with 165 women from Edmonton and 155 from Calgary. We had nine women withdraw from the study and provide no follow-up data. For these analyses, we had 153 exercisers and 154 controls with complete data. Descriptive statistics for baseline and 12-month levels of sex hormones, SHBG and insulin levels, and all anthropometric measures have been reported previously [68], and only a summary is provided here (Table 1).

Women randomized to the exercise and control arms were similar on all demographic, anthropometric, and lifestyle characteristics. Our study population had a mean age of 61 years, were overweight (mean BMI = 29), relatively healthy and fit (VO2max was 27 mL/kg/min), inactive (11 MET-hours/week of recreational activity in the year prior to the study), mainly Caucasian (91% white), married (74%), and fairly well educated (67% greater than high school education).

Mediation

In the present analysis, adjustment for change in percent and total body fat attenuated intervention effects on total estradiol concentrations, but change in intra-abdominal fat area did not (Table 2). For free estradiol, the attenuation was slightly stronger with adjustment for overall body fat change than for intra-abdominal fat change. Intervention effects on SHBG change were attenuated to almost null with adjustment for total and percent body fat and attenuated to a slightly lesser extent with adjustment for intra-abdominal fat change (Table 2). Adjusting for insulin change did not influence the intervention effect. In these same models, however, insulin change was associated with SHBG change when adjusting for intervention effects (p for insulin = 0.001). In exploratory analyses, SHBG change and insulin change were significantly inversely correlated in controls (p = 0.003), but not in exercisers (p = 0.304).

Moderation

The statistical significance of the interaction term between intervention group and each potential moderator is shown in Table 3.

No statistically significant moderation by baseline characteristics was found for estradiol and estrone changes. For SHBG changes, the intervention effect was statistically significantly higher among women with lower baseline fitness levels than among women with higher fitness (continuous, p = 0.005). For testosterone, intervention effects were comparable across dichotomized subgroups; however, fitness (continuous, p = 0.035) and age (continuous, p = 0.038) appeared to moderate the intervention effect in general linear models.

In exploratory analyses, no baseline factor examined as a moderator was significantly correlated with adherence (measured as average weekly duration of exercise) among exercisers.


Discussion

This intervention study investigated potential factors that may mediate and moderate the relation between endogenous sex hormone changes and physical activity among postmenopausal women. This important research question has not been formally examined in previous randomized trials. We found that exercise effects on SHBG and estradiol change were attenuated with adjustment for total and percent body fat change and somewhat attenuated with adjustment for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Baseline physical fitness that appeared to moderate the intervention effects on testosterone and SHBG levels and age seemed to moderate the intervention effects on testosterone levels.

Overall fat loss appeared to mediate SHBG change since, in general linear models, SHBG change was associated with changes in all measures of adiposity, and decreases in percent body fat, total body fat, and intra-abdominal fat each explained most of the total effect of exercise on SHBG change. In another RCT of postmenopausal women, McTiernan et al. [19] similarly found that the greatest 12-month increases in SHBG levels occurred in the subgroup of women who lost >2% body fat, regardless of group assignment. A recent RCT by Monninkhof et al. [20] did not find a significant effect of exercise on SHBG change over 12 months, possibly because the average decrease in fat mass among exercisers (0.8 kg) was lower than in our study (2.4 kg; ref [8]).

We explored insulin reduction as a possible mediator of exercise-induced increases in SHBG levels since insulin lowers SHBG synthesis in the liver [5]. We found that although exercisers experienced a greater decrease in serum insulin concentrations than controls [7], this change did not explain the intervention effect for SHBG. Yet, in exploratory analyses, insulin change correlated with SHBG change in the control group (but not exercisers) and was significantly associated with SHBG change after controlling for intervention effects. Overall, these analyses imply that while insulin changes may have altered SHBG concentrations in some women in the trial, this change does not explain why SHBG changes were greater for exercisers than for controls.

Relatively consistent RCT evidence now points to fat loss as a mediator of exercise-induced estradiol changes. From stratified analyses, McTiernan et al. [19] concluded that combined exercise and fat loss of at least 0.5% may be required to decrease total and free estradiol concentrations; exercise without this level of fat loss did not affect estradiol concentrations. Monninkhof et al. [20] found complete attenuation of an exercise effect on free estradiol levels after adjusting for body fat change, similarly implicating a fat loss mechanism. Our adjusted models showed that overall body fat loss and exercise contributed independently to free and total estradiol changes over 12 months; only a portion of the total effect of the intervention on estradiol change was explained by fat loss. We also found that intra-abdominal fat area did not appear to mediate total estradiol changes, which is of interest to note given that intra-abdominal fat in postmenopausal women relates adversely to adipokine and inflammation levels [21], which are causally related to several chronic diseases [22, 23]. In a comprehensive 2007 report on cancer prevention [2], overall body fatness and abdominal fatness were concluded to be “convincingly” and “probably” associated with an increased risk of postmenopausal breast cancer, respectively.

From a biologic perspective, exercise could lower estradiol concentrations in a variety of ways postmenopause, with loss of body fat proposed as a key mechanism. After menopause, adipose tissue serves as a reservoir of estrogen biosynthesis [24, 25]. Furthermore, several blood biomarkers that occur at higher levels in overweight and obese states such as leptin [26] and IL-6 and TNF-α [27] may induce or stimulate this biosynthesis in some women [28]. It is also possible that adiposity change was merely a surrogate marker of the true mediator of estradiol (and SHBG) changes. Although error in measurement of adiposity change could explain why we did not find that it wholly mediated exercise-induced estradiol changes, the use of valid and reliable measures makes this possibility less plausible. Mechanisms whereby exercise could affect estradiol levels independently of fat loss are as of yet unknown.

To our knowledge, no previous RCT in older women has formally tested moderation of exercise-induced SHBG or sex hormone changes. However, RCTs of 12-month aerobic exercise interventions described by McTiernan et al. [29] and Irwin et al. [30] explored potential moderators of adiposity change, which is relevant to this discussion. Neither McTiernan et al. [29], studying 100 women with a mean age of 54 years, nor Irwin et al. [30], studying 173 postmenopausal women, found statistically significant effect modification by baseline BMI or age. Although we found evidence of moderating effects of age and baseline fitness on testosterone changes, the magnitude of this moderation did not appear to be great since treatment effect ratios were close to 1.0 in subgroups of these characteristics and not statistically significant. The strongest evidence of moderation was for baseline fitness level and SHBG change, in which intervention effects on SHBG appeared to be stronger in women who were less fit at baseline. Exploratory analyses suggested that effect modification did not seem to be explained by differences in adherence but could be explained by differences in fitness change or another factor for which fitness change may be a surrogate. Women with lower baseline fitness level experienced greater improvements in fitness over the 12-month intervention.

There are several limitations to our analyses. First, we did not address all factors that could theoretically impact individual responsiveness to exercise (e.g., genotype) in our moderators analysis. Further limitations apply specifically to the analysis of mediators [31]. For example, mediation might differ across subgroups of exercising women, but we did not have the power to explore this possibility within our data. Our findings may not be generalizable to all postmenopausal women as our study population was free of any major co-morbidities, predominantly Caucasian and educated, and included normal weight women as well as overweight and obese women [6, 8].

In conclusion, these analyses suggest possible mediation of exercise-induced changes in estradiol and SHBG concentrations by loss of overall body fat. Our data further imply that other biologic mechanisms related to exercise were also driving estradiol changes, potentially lowering postmenopausal breast cancer risk, and thus, there is a need to identify those mechanisms. While strong biologic plausibility supports mediation of estradiol changes through fat loss, the understanding of how fat loss relates to SHBG concentrations is less clear. Whether fat loss mediates those changes, or represents a surrogate marker of the true mediator, warrants further study. We found no evidence supporting insulin change as a mediator of exercise-induced changes in SHBG levels. We identified baseline physical fitness and age as possible moderators of exercise-induced testosterone and SHBG changes. This research provides compelling evidence among postmenopausal women of how the relation between physical activity and endogenous sex hormone changes is mediated by body fat loss and the first evidence of moderation by physical fitness and age. Future research will be needed in other populations to corroborate and expand these latter findings.


Notes

Trial registration:

Clinicaltrials.gov identifier: NCT00522262.

The study setup was done by Kim van der Hoek and Marla Orenstein, and the Study Coordinators were Rosemary Crosby and Ame-Lia Tamburrini. The Fitness Centre Managers were Ben Wilson, Lisa Workman, and Diane Cook. The Exercise Trainers were Shannon Hutchins, Kathy Traptow, Shannon Brown, Susan Daniel, Parissa Gillani, Stephanie Sanden, Karen Mackay, and Sandra Olsen. Data preparation was done by Sandra Blitz and Sony Brar. This study was funded by a research grant (#017468) from the Canadian Breast Cancer Research Alliance. Dr. Friedenreich was funded by career awards from Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. Dr. Courneya is supported by the Canada Research Chairs Program.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


References
1.. Lynch BM,Neilson HK,Friedenreich CM. Physical activity and breast cancer preventionRecent Results Cancer ResYear: 2011186134210.1007/978-3-642-04231-7_221113759
2.. Food, nutrition, physical activity, and the prevention of cancer: a global perspectiveYear: 2007Washington, DCAmerican Institute for Cancer Research
3.. Key T,Appleby P,Barnes I,Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studiesJ Natl Cancer InstYear: 200294860661611959894
4.. Neilson HK,Friedenreich CM,Brockton NT,Millikan RC. Physical activity and postmenopausal breast cancer: proposed biologic mechanisms and areas for future researchCancer Epidemiol Biomarkers PrevYear: 2009181112710.1158/1055-9965.EPI-08-075619124476
5.. Plymate SR,Jones RE,Matej LA,Friedl KE. Regulation of sex hormone binding globulin (SHBG) production in Hep G2 cells by insulinSteroidsYear: 198852433934010.1016/0039-128X(88)90136-53074526
6.. Friedenreich CM,Woolcott CG,McTiernan A,et al. Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal womenJ Clin OncolYear: 20102891458146610.1200/JCO.2009.24.955720159820
7.. Friedenreich CM,Neilson HK,Woolcott CG,et al. Changes in insulin resistance indicators, insulin-like growth factors, and adipokines in a year-long trial of aerobic exercise in postmenopausal womenEndocr Relat CancerYear: 201118335736910.1530/ERC-10-030321482635
8.. Friedenreich CM,Woolcott CG,McTiernan A,et al. Adiposity changes after a 1-year aerobic exercise intervention among postmenopausal women: a randomized controlled trialInt J Obes (Lond)Year: 20103542743510.1038/ijo.2010.14720820172
9.. Kraemer HC,Wilson GT,Fairburn CG,Agras WS. Mediators and moderators of treatment effects in randomized clinical trialsArch Gen PsychiatryYear: 2002591087788310.1001/archpsyc.59.10.87712365874
10.. Mackinnon DP,Fairchild AJ. Current directions in mediation analysisCurr Dir Psychol SciYear: 20091811610.1111/j.1467-8721.2009.01598.x20157637
11.. British Columbia Ministry of Health, Canadian Society for Exercise Physiology (2002) Physical activity readiness medical examination
12.. Friedenreich CM,Courneya KS,Neilson HK,et al. Reliability and validity of the Past Year Total Physical Activity QuestionnaireAm J EpidemiolYear: 20061631095997010.1093/aje/kwj11216524954
13.. ACSM’s guidelines for exercise testing and prescriptionYear: 20006Philadelphia, PALippincott Williams & Wilkins
14.. Goebelsmann U,Horton R,Mestman JH,et al. Male pseudohermaphroditism due to testicular 17 -hydroxysteroid dehydrogenase deficiencyJ Clin Endocrinol MetabYear: 197336586787910.1210/jcem-36-5-8674349047
15.. Goebelsmann U,Bernstein GS,Gale JA,et al. Lepow IH,Crozier R,et al.Serum gonadotropin, testosterone, estradiol and estrone levels prior to and following bilateral vasectomyVasectomy: immunologic and pathophysiologic effects in animals and manYear: 1979New YorkAcademic Press165
16.. Probst-Hensch NM,Ingles SA,Diep AT,et al. Aromatase and breast cancer susceptibilityEndocr Relat CancerYear: 19996216517310.1677/erc.0.006016510731105
17.. Rinaldi S,Geay A,Dechaud H,et al. Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculationsCancer Epidemiol Biomarkers PrevYear: 20021110 Pt 11065107112376508
18.. Ware JE,Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36). I. Conceptual framework and item selectionMed CareYear: 19923047348310.1097/00005650-199206000-000021593914
19.. McTiernan A,Tworoger SS,Ulrich CM,et al. Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trialCancer ResYear: 20046482923292810.1158/0008-5472.CAN-03-339315087413
20.. Monninkhof EM,Velthuis MJ,Peeters PH,Twisk JW,Schuit AJ. Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trialJ Clin OncolYear: 200927274492449910.1200/JCO.2008.19.745919687339
21.. Lee CG,Carr MC,Murdoch SJ,et al. Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective studyJ Clin Endocrinol MetabYear: 20099441104111010.1210/jc.2008-070119126626
22.. Pradhan AD,Manson JE,Rossouw JE,et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational studyJAMAYear: 2002288898098710.1001/jama.288.8.98012190368
23.. Pradhan AD,Manson JE,Rifai N,Buring JE,Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitusJAMAYear: 2001286332733410.1001/jama.286.3.32711466099
24.. Simpson ER,Merrill JC,Hollub AJ,Graham-Lorence S,Mendelson CR. Regulation of estrogen biosynthesis by human adipose cellsEndocr RevYear: 198910213614810.1210/edrv-10-2-1362666116
25.. Grodin JM,Siiteri PK,MacDonald PC. Source of estrogen production in postmenopausal womenJ Clin Endocrinol MetabYear: 197336220721410.1210/jcem-36-2-2074688315
26.. Magoffin DA,Weitsman SR,Aagarwal SK,Jakimiuk AJ. Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling womenGinekol PolYear: 19997011710349800
27.. Purohit A,Reed MJ. Regulation of estrogen synthesis in postmenopausal womenSteroidsYear: 2002671297998310.1016/S0039-128X(02)00046-612398994
28.. Maccio A,Madeddu C,Mantovani G. Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectivesObes RevYear: 200910666067010.1111/j.1467-789X.2009.00592.x19460113
29.. McTiernan A,Sorensen B,Irwin ML,et al. Exercise effect on weight and body fat in men and womenObesity (Silver Spring)Year: 20071561496151210.1038/oby.2007.17817557987
30.. Irwin ML,Yasui Y,Ulrich CM,et al. Effect of exercise on total and intra-abdominal body fat in postmenopausal women: a randomized controlled trialJAMAYear: 2003289332333010.1001/jama.289.3.32312525233
31.. Bullock JG,Green DP,Ha SE. Yes, but what’s the mechanism? (don’t expect an easy answer)J Pers Soc PsycholYear: 201098455055810.1037/a001893320307128

Tables
[TableWrap ID: Tab1] Table 1 

Baseline characteristics of randomized participants in the ALPHA Trial, Alberta, Canada, 2003–2007, n = 320


Baseline characteristics  Exercisers (n = 160) Controls (n = 160)
Mean ± SD Mean ± SD
Age (yrs) 61.2 ± 5.4 60.6 ± 5.7
Body composition measurements
 Body mass index (kg/m2) 29.1 ± 4.5 29.2 ± 4.3
 Intra-abdominal fat area (cm2) 101.4 ± 55.4 103.2 ± 56.0
 Total body fat (kg) 30.9 ± 8.2 31.3 ± 8.6
 Percent body fat 42.2 ± 4.9 42.4 ± 5.7
n (%) n (%)
Full-time employment 82 (55) 79 (51)
Education (>high school) 112 (70) 102 (64)
Median (IQR) Median (IQR)
Sex hormone concentration
 Estradiol (pg/mL) 9.0 (7.0–12.0) 10.0 (7.0–14.0)
 Estrone (pg/mL) 32.0 (24.0–44.0) 32.0 (22.5–44.5)
 Sex hormone–binding globulin (nmol/L) 41.5 (30.0–57.0) 39.5 (28.0–51.5)
 Androstenedione (pg/mL) 576 (434–779) 547 (417–736)
 Testosterone (ng/dL) 24.3 (16.8–32.8) 23.3 (17.5–32.4)
 Free estradiol (pg/mL) 0.23 (0.17–0.31) 0.24 (0.18–0.36)
 Free testosterone (ng/dL) 0.36 (0.24–0.48) 0.36 (0.25–0.49)
Metabolic hormone concentration
 Insulin (μIU/mL) 6.2 (3.8–9.5) 5.7 (3.4–8.9)

[TableWrap ID: Tab2] Table 2 

Exercise intervention effects on estradiol and sex hormone–binding globulin before and after adjustment for hypothesized mediators


Outcome Before adjustment Hypothesized mediator After adjustment
Treatment effect ratio of Exercise/Control (95% CI) a Treatment Effect Ratio of Exercise/Control (95% CI) a p for mediatorb
Estradiol
0.93 (0.88–0.98) Percent body fat 0.95 (0.90–1.00) 0.005
Total body fat 0.95 (0.90–1.00) 0.005
Intra-abdominal fat area 0.93 (0.89–0.99) 0.176
Sex hormone–binding globulin
1.04 (1.02–1.07) Percent body fat 1.01 (0.98–1.03) <.001
Total body fat 1.01 (0.98–1.03) <.001
Intra-abdominal fat area 1.02 (0.99–1.05) <.001
Insulin 1.04 (1.01–1.06) 0.001
Free estradiol
0.91 (0.87–0.96) Percent body fat 0.94 (0.89–1.00) <.001
Total body fat 0.94 (0.89–1.00) <.001
Intra-abdominal fat area 0.93 (0.88–0.98) 0.051

aThe treatment effect ratio was calculated from a general linear model for each biomarker outcome, estimating a parameter whose anti-logarithm corresponds to the ratio of adjusted geometric means of the biomarker for the exercise intervention group over the control group: this ratio was assumed to be common at 6 months and 12 months postrandomization. A ratio <1.0 indicates lower hormone or SHBG levels in exercisers relative to controls at 6 and 12 months; a ratio >1.0 indicates a higher hormone or SHBG levels in exercisers; and a ratio equal to 1.0 indicates no difference between exercisers and controls. The model after-adjustment has one more covariate: change of hypothesized mediator at 6 and 12 months, compared to the model before-adjustment

bP value for the association between mediator and outcome after adjustment for intervention assignment

Sample size N: exercise group, baseline = 160, 6 month = 154, 12 month = 154; control group, baseline = 160, 6 month = 154, 12 month = 156


[TableWrap ID: Tab3] Table 3 

Exercise intervention effects on sex hormones, stratified by potential moderators


Moderatora nb Treatment effect ratioc (95% CI)
Level Estradiol Estrone Testosterone SHBG
Physical fitness (VO2max)
 ≤27.5 mL/kg/min 82/80 0.98 (0.92–1.04) 0.98 (0.92–1.05) 0.97 (0.92–1.03) 1.06 (1.02–1.09)
 >27.5 77/79 0.89 (0.82–0.96) 0.99 (0.93–1.05) 1.01 (0.95–1.07) 1.03 (0.99–1.07)
 pe 0.573 0.175 0.035 0.005
Age
 ≤60 years 73/81 0.91 (0.83–0.99) 1.01 (0.95–1.07) 1.03 (0.97–1.10) 1.04 (1.00–1.08)
 >60 87/78 0.96 (0.91–1.02) 0.96 (0.90–1.03) 0.95 (0.90–1.01) 1.04 (1.01–1.08)
 pe 0.712 0.200 0.038 0.480
Time since menopause
 <10 years 80/69 0.91 (0.84–0.99) 1.02 (0.96–1.08) 1.02 (0.96–1.08) 1.05 (1.02–1.09)
 ≥10 78/90 0.96 (0.91–1.02) 0.96 (0.90–1.03) 0.95 (0.90–1.00) 1.04 (1.00–1.08)
 pe 0.673 0.776 0.609 0.477
Previous HRT use
 Yes 75/71 0.92 (0.87–0.99) 0.97 (0.90–1.04) 0.96 (0.90–1.02) 1.02 (0.98–1.06)
 No 84/88 0.94 (0.87–1.01) 1.00 (0.95–1.06) 1.01 (0.95–1.07) 1.07 (1.03–1.10)
 pe 0.754 0.480 0.326 0.149
Self-rated healthd
 Low 88/76 0.93 (0.86–1.01) 1.01 (0.94–1.07) 0.97 (0.91–1.03) 1.05 (1.02–1.09)
 High 71/81 0.92 (0.86–0.98) 0.97 (0.92–1.04) 1.02 (0.96–1.08) 1.04 (1.00–1.08)
 pe 0.516 0.441 0.968 0.923
Past year recreational activity
 <7 MET–h/week 87/74 0.88 (0.82–0.95) 0.96 (0.90–1.02) 0.95 (0.90–1.01) 1.05 (1.01–1.09)
 ≥7 73/85 0.97 (0.90–1.05) 1.01 (0.94–1.07) 1.02 (0.96–1.09) 1.04 (1.00–1.08)
 pe 0.642 0.656 0.637 0.508
Body mass index
 <28.7 kg/m2 80/77 0.95 (0.87–1.03) 1.04 (0.97–1.11) 1.03 (0.97–1.09) 1.03 (0.99–1.07)
 ≥28.7 80/82 0.91 (0.86–0.96) 0.94 (0.89–1.00) 0.95 (0.90–1.01) 1.06 (1.02–1.10)
 pe 0.714 0.066 0.179 0.586
Estradiol
 <10 pg/mL 86/70 0.97 (0.90–1.04)
 ≥10 74/89 0.90 (0.84–0.97)
 pe 0.935
Estrone
 <32 pg/mL 87/85 1.01 (0.95–1.08)
 ≥32 73/74 0.96 (0.90–1.02)
 pe 0.180
Testosterone
 <24 ng/dL 77/82 0.99 (0.93–1.06)
 ≥24 83/77 0.99 (0.93–1.04)
 pe 0.497
SHBG
 <40 nmol/L 76/85 1.06 (1.02–1.10)
 ≥40 84/74 1.03 (0.99–1.06)
 pe 0.764

SHBG sex hormone–binding globulin

aLevel of potential moderator at baseline

bNumber of exercisers/number of controls

cThe treatment effect ratio was calculated from a general linear model for each biomarker outcome, estimating a parameter whose anti-logarithm corresponds to the ratio of adjusted geometric means of the biomarker for the exercise intervention group over the control group: this ratio was assumed to be common at 6 months and 12 months postrandomization. A ratio <1.0 indicates lower hormone or SHBG levels in exercisers relative to controls at 6 and 12 months; a ratio >1.0 indicates higher hormone or SHBG levels in exercisers; and a ratio equal to 1.0 indicates no difference between exercisers and controls

dSelf-rated health measured by self-administered questionnaire using the SF-36 scale (range, 0–100) where low was a score of <82 and high was ≥82

eStatistical significance of the interaction term between intervention group and the potential moderator. Note that all moderators except for previous HRT use were treated as continuous variables when calculating this p value for heterogeneity



Article Categories:
  • Original Paper

Keywords: Keywords Exercise, Gonadal steroid hormones, Sex hormone–binding globulin, Randomized controlled trial, Breast neoplasms.

Previous Document:  Risk of lung cancer in relation to contiguous windows of endotoxin exposure among female textile wor...
Next Document:  Cytophagic histiocytic panniculitis with haemophagocytosis in a patient with familial multiple lipom...