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Physical Activity and Postmenopausal Breast Cancer:Proposed Biologic Mechanisms and Areas forFuture Research Heather K. Neilson,1 Christine M. Friedenreich,1 Nigel T. Brockton,1 and Robert C. Millikan2 1Division of Population Health and Information, Alberta Cancer Board, Calgary, Canada; and 2Department of Epidemiology andLinberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina Convincing evidence now supports a probable pre- cer risk through interrelated mechanisms. The most ventive role for physical activity in postmenopausal convincing epidemiologic evidence supported associa- breast cancer. The mechanisms by which long-term phy- tions between postmenopausal breast cancer risk and sical activity affect risk, however, remain unclear. The BMI, estrogens, and androgens, respectively. In relation aims of this review were to propose a biological model to physical activity, associations were most convincing whereby long-term physical activity lowers postmeno- for BMI, estrone, insulin resistance, and C-reactive pausal breast cancer risk and to highlight gaps in the protein. Only BMI and estrone were convincingly (or epidemiologic literature. To address the second aim, probably) associated with both postmenopausal breast we summarized epidemiologic literature on 10 proposed cancer risk and physical activity. There is a need for biomarkers, namely, body mass index (BMI), estrogens, prospective cohort studies relating the proposed bio- androgens, sex hormone binding globulin, leptin, adi- markers to cancer risk and for long-term exercise ponectin, markers of insulin resistance, tumor necrosis randomized controlled trials comparing biomarker factor-A, interleukin-6, and C-reactive protein, in rela- changes over time, specifically in postmenopausal tion to postmenopausal breast cancer risk and physical women. Future etiologic studies should consider inter- activity, respectively. Associations were deemed ‘‘con- actions among biomarkers, whereas exercise trials vincing,'' ‘‘probable,'' ‘‘possible,'' or ‘‘hypothesized'' should explore exercise effects independently of weight using set criteria. Our proposed biological model illus- loss, different exercise prescriptions, and effects on trated the co-occurrence of overweight/obesity, insulin central adiposity.
(Cancer Epidemiol Biomarkers Prev resistance, and chronic inflammation influencing can- 2009;18(1):11– 27) In 2004 the lifetime probability of developing invasive (4), whereby habitual activity may lower risk by appro- breast cancer for women in Canada was 11% or 1 in 9, ximately 20% (7). The evidence in premenopausal more than any other cancer in women aside from women has been generally weaker (4, 5). The mecha- nonmelanoma skin cancer (1). In 2004 in the United nisms by which long-term physical activity lowers post- States, invasive breast cancer was the most commonly menopausal breast cancer risk, however, remain unclear.
diagnosed cancer in women (age-adjusted incidence Mechanistic insight, ideally from biomarker studies (8), rate at 118 per 100,000 women; ref. 2). Although several would add biological plausibility to the association, risk factors are proposed for breast cancer, low levels of guide future epidemiologic research, identify new targets physical activity may be one of the most modifiable.
for interventions, and inform public health recommen- Excess body weight and low physical activity together dations for lowering breast cancer risk.
may account for one quarter to one third of all breast The aims of our review were to propose a biological cancer cases (3). From the substantial epidemiologic model whereby long-term physical activity lowers post- literature on physical activity and breast cancer (3-6), menopausal breast cancer risk and to highlight gaps in convincing evidence now supports a ‘‘probable'' preven- the epidemiologic literature. To address the second aim, tive role for physical activity in postmenopausal women we summarized the existing epidemiologic literatureon the following 10 biologically plausible, candidatebiomarkers (anthropometric and blood), in relation to Received 8/15/08; revised 10/5/08; accepted 10/27/08.
postmenopausal breast cancer risk and physical activity, Grant support: CMF is supported by an Alberta Heritage Foundation for Medical respectively: body weight or body mass index (BMI), Research Health Senior Scholar Award. R.C. Millikan is supported by the SpecializedProgram of Research Excellence in Breast Cancer NIH Grant P50-CA58223.
estrogens, androgens, sex hormone binding globulin Requests for reprints: Christine Friedenreich, Division of Population Health, (SHBG), leptin, adiponectin, markers of insulin resistance Alberta Cancer Board, 1331-29 Street NW, Calgary, Alberta, Canada T2N 4N2.
(i.e. insulin, glucose, C-peptide, and glycosylated hemo- Phone: 403-521-3841; Fax: 403-270-8003. E-mail: chrisf@cancerboard.ab.caCopyright D 2009 American Association for Cancer Research.
globin), tumor necrosis factor a (TNF-a), interleukin-6 (IL-6), and C-reactive protein (CRP). Although many Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Physical Activity and Postmenopausal Breast Cancer candidate biomarkers exist (9-14), the plausibility of our types and we believed all of the associations to be chosen biomarkers has been discussed in recent literature biologically plausible. Furthermore, we did not assess (9, 13, 15) and their responses to exercise have been physical activity methods or adjustment for potential tested (16-20) or are currently under investigation (9) in confounders in the individual studies as these assess- various exercise intervention trials for postmenopausal ments were beyond the scope of this review. An asso- breast cancer prevention. Insulin-like growth factor-1 ciation was deemed ‘‘convincing'' if it was supported by was not included in our review because most previous at least two cohort studies or trials (i.e., randomized or studies in older women have not shown decreased nonrandomized) and the expected association was found insulin-like growth factor-1 with increasing physical consistently across all analyses, or if the association was activity (20, 21). Moreover, at least two reviews of the generally supported by a large body of epidemiologic epidemiologic literature failed to show significantly literature and/or public health guidelines. An associa- altered breast cancer risk in postmenopausal women tion was considered ‘‘probable'' if two or more cohort with higher insulin-like growth factor-1 levels (22, 23).
studies or trials were conducted and most of the analyses Likewise, we excluded mammographic density from our supported the same expected association. ‘‘Possible'' biological model because recent research has generally described associations based on two or more cohort shown no association between physical activity and studies or trials or five or more case-control, nested case- breast density (24-30).
control, or case-cohort studies and/or 50% of theanalyses or less supporting the same expected associa-tion. An association was ‘‘hypothesized'' if supported by Materials and Methods a limited number of studies and/or very few analyses, ifany, showed the expected association. We summarized In February 2008 we searched the published literature each study's findings very simply in terms of ‘‘positive'' using PubMed (NIH). To identify studies we queried or ‘‘negative'' based on the direction of the association medical subject headings (MeSH) for each hypothesized and whether or not the adjusted results reached biomarker combined with terms for breast cancer (MeSH statistical significance (P V 0.05).
term ‘‘Breast Neoplasms'') and physical activity (‘‘phys-ical activity'' or MeSH terms ‘‘Motor Activity'' or ‘‘Exercise''), respectively. Hypothesized biomarker infor-mation was retrieved using the following MeSH terms: Body Weight Measures. A strong biological rationale ‘‘Estrogens,'' ‘‘Androgens,'' ‘‘Sex-hormone binding glob- and wealth of epidemiologic evidence now support a ulin,'' ‘‘C-reactive protein,'' ‘‘Leptin,'' ‘‘Adiponectin,'' role for elevated body weight in increasing postmeno- ‘‘Interleukin-6,'' ‘‘Tumor necrosis factor-alpha,'' ‘‘Insu- pausal breast cancer risk. Overweight and obesity could lin,'' "Insulin resistance," ‘‘Glucose,'' ‘‘C-peptide,'' ‘‘He- lead to cancer through a number of pathways, including moglobin A, Glycosylated,'' ‘‘Hyperinsulinism,'' ‘‘Body higher levels of circulating sex hormones, insulin weights and measures,'' ‘‘Body composition,'' and resistance, chronic inflammation, and/or lower levels ‘‘Body weight.'' We limited our electronic search to of SHBG and adiponectin (Table 1), although the exact English language publications in humans. Due to the mechanisms are unknown.
extensive literature on physical activity and insulin As expected, our search of the review literature resistance, physical activity and body weight, and breast supported a convincing positive association between cancer and body weight, we restricted the latter three postmenopausal breast cancer risk and elevated BMI searches to English language review articles and meta- (Table 2). A 2007 review of 24 cohort studies and 56 case- analyses in adults. With respect to the remaining topics, control studies in postmenopausal women (4) provided we reviewed original articles reporting results explicitly strong evidence of increased risk with increasing BMI for postmenopausal women. We excluded intervention based on consistent findings and clear dose-response trials in cancer survivors and studies in diseased women relations. Similarly, a 2008 meta-analysis of 31 prospec- (unless they were type 2 diabetics, whom we included), tive studies found a 12% increase in risk of postmeno- trained athletes, or the severely obese. Studies presenting pausal breast cancer for every 5 kg/m2 increase in BMI results only for women on hormone replacement ther- [relative risk, 1.12; 95% confidence interval (95% CI), apy were also excluded. Furthermore, if postmenopausal 1.08-1.16; ref. 31]. In general, earlier reviews reported status was ambiguous or results were not stratified by higher risk with adult weight gain (32, 33) and increas- menopausal status, then the article was excluded. If ing weight and/or BMI for postmenopausal women menopausal status was not stated but the minimum age (3, 33-36). A 2001 meta-analysis of 13 studies in post- of participants was z55 y, however, the study was menopausal women showed a significantly increased included. Acute exercise trials (<4 wk duration) or trials risk of breast cancer by 2% per 1 kg/m2 increase in BMI intervening in both exercise and diet were similarly (37). Subsequently, a 2003 pooled analysis of eight excluded from our review in order to isolate the effects prospective studies of postmenopausal women (38) of long-term physical activity from weight loss. The found the relative risk of breast cancer to be 1.19 (95% review was not restricted to any particular type or CI, 1.05-1.34) for every 5 kg/m2 increase in BMI.
intensity of physical activity.
However, when adjusted for free estradiol, the risk We classified the epidemiologic evidence using a approached unity (relative risk, 1.02; 95% CI, 0.89-1.17).
scheme adapted from the American Institute of Cancer In the same analysis, the mean concentration of estrogen Research/World Cancer Research Fund's recent compre- metabolites in obese women (BMI z30.0) was between hensive report on physical activity and cancer prevention 60% and 219% higher than in thin women (BMI <22.5), (4). Unlike the report, however, we did not assess study showing the important, presumably causal path from quality or study heterogeneity within or among study body weight to circulating estrogen levels (Table 1).
Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Cancer Epidemiology, Biomarkers & Prevention Table 1. Possible mechanisms relating commonly proposed biomarkers to postmenopausal breast cancer risk andphysical activity Proposed biomarker Possible role in postmenopausal breast cancer Possible impact of physical activity in postmenopausal women Adipose tissue contains higher levels of aromatase Reduces adiposity thereby lowering the capacity which converts androgens to estrogens (57).
for conversion of androgens to estrogens by Estrogens are mitogens in the breast, stimulating aromatase and lowering circulating estrogen mammary cell proliferation through estrogen levels (10, 221).
receptor – mediated transcriptional activity and by Reduces insulin levels thereby increasing SHBG activation of intracellular signaling pathways (48, 57).
levels (73-75) which may decrease estradiolbioavailability.
Testosterone and androstenedione may increase Decreases testosterone levels through loss of body risk upon conversion to estradiol and estrone, fat. Decreased adiposity lowers levels of 17h- respectively, in adipose tissue (58, 222).
hydroxysteroid dehydrogenase enzyme which Androgens also act directly on breast cells by binding converts androstenedione to testosterone in s.c.
to the androgen receptor (65), a ligand-dependent and intra-abdominal fat (228), thereby lowering transcription factor expressed in the majority of breast cancers (223, 224).
Reduces adiposity thereby lowering the capacity There may be synergy between estrogens and for conversion of androgens to estrogens by androgens in increasing breast cancer risk (69).
aromatase and lowering circulating estrogen The exact mechanism in postmenopausal breast levels (10, 221).
cancer is unclear (69, 225). In vitro, androgens can Reduces insulin levels thereby increasing SHBG directly stimulate or inhibit breast cancer cell levels (73-75) which may decrease testosterone proliferation depending on the cell line (69, 226, 227).
Some clinical data support a protective role forandrogens in breast cancer (227).
SHBG binds to estradiol and testosterone (55) thereby Reduces insulin levels which increases circulating reducing their bioavailabilities; may act as a negative SHBG (73, 229), thereby decreasing the modulator of estradiol (54).
bioavailabilities of estradiol and testosterone.
Insulin Resistance Hyperinsulinemia is associated with decreased An acute bout of exercise enhances insulin plasma SHBG (73, 229), thereby increasing sex sensitivity and glucose uptake mainly on account of skeletal muscle activity; however, the effects Insulin exerts mitogenic effects in breast cancer cells tend to dissipate within days (78).
in vitro; (230, 231) may synergize with estrogen Prolonged high intensity exercise training can sustain insulin sensitivity (76, 78) and protect Insulin resistance and hyperinsulinemia are strongly against development of type 2 diabetes (77) related to obesity,(233) and particularly intra- perhaps by reducing abdominal fat, increasing abdominal fat (73, 234). Insulin resistance has been skeletal muscle mass, increasing glucose associated with increased leptin, TNF-a, adipose transport into the muscle,(235) or decreasing tissue – derived IL-6, and decreased adiponectin, fatty acid synthesis (76, 78).
respectively (15, 117).
Overweight and obesity generally results in: higher Reduces body weight (41) and decreases central levels of sex hormones (71, 236, 237); adiposity in some populations (239) including higher levels of aromatase, which converts androgens postmenopausal women (17, 107, 108, 216, 240).
to estrogens in adipose tissue, and therefore higherlevels of total estradiol (57, 75, 238); more abdominal fat and thus more 17h-hydroxysteroid dehydrogenase, which regulates the conversion ofandrostenedione to testosterone (228); chronic release of free fatty acids from adipose tissue, resulting in reduced uptake of glucose by thetissues and consequently, increased circulatinginsulin (57, 238); lower levels of SHBG in response to hyperinsulinemia and thus, higher circulating levels of bioavailableestradiol and testosterone (57, 238); greater release of leptin, IL-6, and TNF-a from adipose tissue and decreased adiponectin (57, 111, 141, 238).
Not surprisingly, clinical practice guidelines for weight by 3.6% on average (41). In a meta-analysis of treatment of overweight and obesity in the United States nine pedometer-based interventions, there was a strong (39) and Canada (40) support a convincing association dose-response relation whereby longer intervention between long-term physical activity and weight loss duration was associated with greater weight loss (44).
(Table 3). Although calorie restriction induces more Another review of eight recent (2000-2006) exercise weight loss than exercise alone (41), both countries randomized control trials (RCT) suggested that longer advocate long-term regular exercise to induce modest duration of physical activity is optimal for decreasing weight loss in overweight and obese adults. Exercise is body weight and adiposity (45).
also recommended to maintain weight loss (40, 42, 43). Ameta-analysis of 25 years of lifestyle weight loss Estrogens and SHBG. Endogenous estrogen status has programs specifically showed that aerobic exercise alone become a well-established risk factor for postmenopausal (mean, 15.6 weeks) decreased BMI by 0.8 and initial breast cancer (46) regardless of individual risk (predicted Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Physical Activity and Postmenopausal Breast Cancer Table 2. Results from epidemiologic studies of proposed biomarkers and breast cancer risk in postmenopausalwomen Proposed biomarker Type of study design, study results (F/NA) and number of analyses 4 (125, 204, 245, 250) Reviews of the epidemiologic literature support positive associations between postmenopausal breast cancer risk and BMI and/or body weight (3, 4, 31, 33-38).
NOTE: +, positive association and P V 0.05; , negative association and P V 0.05; NA, no association and P > 0.05.
*Original studies included in pooled analyses were exclusive from studies referenced elsewhere in the table. The pooled analysis by Key et al. (59) includedonly prospective studies in postmenopausal women: six studies on estrone, nine on estradiol, seven on SHBG, seven on testosterone, and five onandrostenedione. An update on one cohort included the pooled analysis (253) was subsequently published (254) but was not included in the table to avoiddouble counting.
by a modified Gail model, the Rosner and Colditz model, It is worth noting that most physical activity studies were or family history of breast cancer; ref. 47) with possible cross-sectional in nature (5 of 8 studies on estrone, 7 of influence on the initiation, promotion, and progression 10 studies on estradiol, 5 of 9 studies on SHBG), which is of breast cancer (48). Furthermore, the successful use of a limited study design because the temporal sequence of antiestrogenic drugs in reducing breast cancer incidence cause and effect cannot be shown.
rates supports a role for estrogens in breast cancer etio- It is unclear whether or not physical activity lowers logy (49-51). Several estrogen metabolites may influence estrogen levels independently of weight loss. Some cross- breast cancer risk (52) including estrone, estrone sulfate, sectional studies have found significant inverse associa- and 17h-estradiol (estradiol), the most biologically active tions between physical activity and estrogen levels even endogenous estrogen (53). Higher SHBG might lower after controlling for BMI or adiposity (61-64), suggest- risk by acting as a negative modulator of estradiol (54) ing an independent role for physical activity. Yet in a and by reducing estrogen bioavailability (55). The most 12-month RCT (18), postmenopausal women assigned to common hypothesis linking postmenopausal breast can- an exercise group who lost z0.5% body fat experienced cer to estrogens relates to adiposity (Table 1). The main decreased estrone, estradiol, free estradiol and increased source of circulating estrogens, for postmenopausal SHBG, whereas women who did not lose body fat women who do not use hormone replacement therapy, experienced increased estrogen levels.
derives from androgen aromatization in the peripheraltissues such as bone, muscle, brain, and most notably, Androgens. As for estrogens, a growing body of adipose tissue (56-58).
epidemiologic evidence supports a positive association As expected, our review of the literature revealed a between androgen levels and postmenopausal breast convincing association between postmenopausal breast cancer risk (46). Androgens are the most abundant sex cancer and estrone and a probable association with steroid hormones in postmenopausal women, with estradiol (Table 2). Some of the strongest evidence testosterone being one of the most powerful natural stemmed from a pooled analysis of prospective studies forms (65). Before and after menopause, adrenal- or in postmenopausal women (59), in which the odds ratio ovarian-derived androstenedione gives rise to testoster- for breast cancer was 2.00 (95% CI, 1.47-2.71) for the one (and its derivative, dihydrotestosterone) in the highest versus the lowest quintiles of total estradiol; for ovaries and in other tissues such as adipose and breast estrone the odds ratio was 2.19 (95% CI, 1.48-3.22). The (65-68). As with estradiol, testosterone binds reversibly to evidence for SHBG was less convincing, deemed possible SHBG rendering it biologically inactive (55). The aroma- using our criteria, with the pooled analysis resulting in tase enzyme converts testosterone to estradiol, and an odds ratio of 0.66 (95% CI, 0.43-1.00) reaching only androstenedione to estrone, within the adipose tissue of borderline statistical significance (59).
postmenopausal women (56).
In relation to physical activity, associations were rated It remains unclear whether increased risk results from probable for estrone but only possible for estradiol and androgens increasing breast cell growth directly or SHBG (Table 3). Two RCTs examined estrone and indirectly via estrogen production (Table 1; ref. 69). For estradiol in relation to physical activity with one RCT example, one prospective study in postmenopausal showing no association (60) and the other showing sig- women found little association between androgens and nificant inverse associations with both metabolites (18).
breast cancer risk after controlling for estrogen levels Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Cancer Epidemiology, Biomarkers & Prevention Table 2. Results from epidemiologic studies of proposed biomarkers and breast cancer risk in postmenopausalwomen (Cont'd) Type of study design, study results (F/NA) and number of analyses Nested case-control or case-cohort (70). Likewise, respective adjustments for estrone, estra- insulin resistance can coincide with normal or impaired diol, and free estradiol (but not testosterone or andros- glucose tolerance, it also increases risk of type 2 diabetes tenedione) substantially weakened associations between and is a key component of the metabolic syndrome, BMI and postmenopausal breast cancer risk in one two conditions that are modifiable by physical activity nested case-control study (71). However, adjustment for (77, 81). Genetic and environmental factors contribute estradiol levels only slightly attenuated the relative risk to both insulin resistance and the metabolic syndrome; associated with testosterone in a pooled analysis of obesity, however, and particularly intra-abdominal prospective studies (59) and at least one other cohort adiposity are also considered important determinants study (72), thus supporting an independent mechanism of risk (77, 82).
for androgens.
A causal link between insulin resistance and post- Our review found probable associations between menopausal breast cancer risk is biologically plausible postmenopausal breast cancer risk and androstenedione (Table 1). Furthermore, in one meta-analysis, diabetes and testosterone, respectively, because most studies mellitus (largely type 2) was associated with a significant supported positive relations (Table 2). In a pooled (16%) increase in postmenopausal breast cancer risk (83).
analysis of prospective studies, postmenopausal women Our review suggested a possible increased risk of post- in the highest quintiles of serum testosterone and menopausal breast cancer with higher levels of serum androstenedione concentrations, respectively, had more insulin, glucose, and C-peptide (a marker of pancreatic than double the risk of developing breast cancer insulin secretion; ref. 84), respectively (Table 2). Of the compared with women in the lowest quintiles (relative 14 studies measuring at least one of these markers in risk, 2.22; 95% CI, 1.59-3.10 for testosterone; relative risk, postmenopausal women, seven found at least one 2.15; 95% CI, 1.44-3.21 for androstenedione; ref. 59). In significant positive association (85-91), whereas the the same analysis, a doubling of androgen levels remainder showed no association (92-98). Also one large produced an estimated 20% to 40% increase in breast cohort study (99) revealed a weak inverse association cancer risk.
between postmenopausal breast cancer risk and HbA1C, a Physical activity could lower testosterone levels by measure of long-term blood glucose levels (100).
decreasing adiposity or by increasing circulating SHBG In contrast to its possible association with breast can- (refs. 73-75; Table 1). However, our literature review cer risk, we classified the link between physical acti- suggested only possible inverse associations between vity and insulin resistance as convincing (Table 3) based physical activity and serum testosterone and serum on the scientific consensus (7, 76, 101-104). Specifically, androstenedione (Table 3). Similar to the estrogen a statement by the American Diabetes Association, the literature, much of this evidence was derived from North American Association for the Study of Obesity, cross-sectional studies (4 of 8 studies on testosterone, and the American Society for Clinical Nutrition (102), 4 of 6 studies on androstenedione) and hence, causal and others promote moderate weight loss via regular inference is limited.
aerobic, and possibly resistance (103), exercise to im-prove insulin sensitivity (105) and prevent diabetes Insulin Resistance. Insulin resistance describes the (7, 76, 102, 104). The effect of exercise may be strongest reduced effectiveness of insulin to regulate blood for those with impaired (versus normal) glucose toler- glucose, primarily via skeletal muscle (76, 77). When ance (76) and when followed at higher doses (106), tissues cease to respond effectively to insulin, glucose higher intensity (107), or when as combined aerobic/ uptake is reduced while the liver increases glucose resistance exercise versus aerobic exercise alone (108).
biosynthesis, resulting in hyperglycemia. The pancreaticresponse to high blood glucose is increased insulin secre- Adipokines and Inflammatory Markers. Adipokines tion, resulting in hyperinsulinemia (78-80). Although (adipocytokines) are a group of biologically active Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Physical Activity and Postmenopausal Breast Cancer Table 3. Results from epidemiologic studies of proposed biomarkers and physical activity in postmenopausalwomen Proposed biomarker in blood Type of study design, study results (F/NA) and number of analyses 5 (61, 63, 64, 258, 259) 4 (63, 258, 259, 262) Insulin, glucose, C-peptide Reviews generally promote moderate weight loss with exercise to improve insulin sensitivity (101, 105) and prevent diabetes (7, 76, 102, 104).
Clinical guidelines for weight loss in the United States (39) and Canada (40) advocate long-term regular exercise to induce modest weight loss in overweight and obese adults.
, and NA P > 0.05.
*The associations deemed ‘‘+'' or ‘‘ '' were based on the change observed in exercisers versus the change observed in controls with the exception of theRCT described by Giannopoulou et al. (129),which did not include a control arm; rather, the results at baseline were compared with the end of studywithin the exercise only arm.
polypeptides produced by adipocytes or adipose tis- ered in 1994 (121), its role in cancer etiology is only sue; they include leptin, adiponectin, TNF-a, and IL-6 recently appreciated. Adipose tissue is quantitatively the (109-111). CRP is not an adipokine but is produced in the most important source of leptin and the primary liver in response to TNF-a and IL-6 levels (112), which determinant of circulating leptin levels (122-124). Leptin are all considered common indicators of inflamma- is widely known for its ability to counteract obesity tion (113). Chronic inflammation is an acknowledged by inducing satiety and limiting caloric intake (123), risk factor for several cancers (114), and obesity (112) and but paradoxically, human obesity is associated with the metabolic syndrome (115) represent low-grade, sys- higher levels of circulating leptin, possibly signifying temic inflammatory states with elevated levels of inflam- leptin resistance (57, 122). Considerable in vitro evi- matory markers. The sustained proliferative activity, dence implicates leptin as a risk factor for breast cancer microenvironmental changes, and oxidative stress asso- (Table 4), either by direct mitogenic action on breast cells ciated with chronic inflammation could act together to or perhaps indirectly, for example, by increasing estro- deregulate normal cell growth and development, thereby gen production or by promoting insulin resistance.
promoting initiated cells toward malignancy (116).
Despite biological plausibility, we classified the Postmenopausal breast cancer risk is positively asso- epidemiologic evidence relating leptin to postmeno- ciated with increased BMI (Table 2), and adipokines pausal breast cancer risk as possible (Table 2). Of the similarly exhibit strong positive correlations with BMI seven studies we reviewed, only two case-control studies (15), hyperinsulinemia, insulin resistance, and type 2 (125, 126) found significant positive associations. We did diabetes (conditions related to overweight and obesity; not identify any cohort studies in postmenopausal refs. 15, 117). Several biological mechanisms impli- women. In contrast, the relation between higher physical cate adipokines in breast cancer etiology (Table 4), but activity and decreased leptin was deemed probable the extent to which adipokines influence breast can- in our review (Table 3). Although only five studies were cer risk directly or act as biomarkers of increased identified, all five were prospective trials and four adiposity, insulin resistance, and chronic inflammation, (16, 127-129) produced significant decreases in leptin.
is unresolved.
Moreover, reviews have suggested that the greatest Regular physical activity may reduce inflammation impact on leptin is achieved by exercise training of independently of fat loss (118), but the mechanisms are longer duration, extending beyond 12 weeks, and at unknown. One RCT in postmenopausal women (118) higher intensities (130, 131).
found that a 6-month weight loss intervention, compris- Adiponectin. Adiponectin was first described in 1995 as ing a hypocaloric diet and exercise, significantly de- the most abundant gene product of human adipocytes creased plasma TNF-a, IL-6, and CRP whereas significant (132). It is now gaining recognition as a predictive changes were not observed in the group receiving only indicator of abdominal fat and obesity-related sequelae the diet intervention. Interestingly, the two groups such as the metabolic syndrome (133) and now, possibly, experienced similar losses in body weight and adipose breast cancer. Although adiponectin is produced only tissue. Furthermore, a recent review article concluded by adipocytes (57, 134), unlike other adipokines, it has that physical fitness generally decreases inflammatory a strong inverse correlation with adiposity (135); con- markers even after adjusting for adiposity (119).
sequently, weight loss increases adiponectin levels Leptin. Leptin is both a neurohormone and a member (136, 137). The relation may occur in part because IL-6 of the cytokine superfamily (120). Although first discov- and TNF-a, which increase in obesity (138), are potent Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Cancer Epidemiology, Biomarkers & Prevention Table 3. Results from epidemiologic studies of proposed biomarkers and physical activity in postmenopausalwomen (Cont'd) Type of study design, study results (F/NA) and number of analyses ConvincingConvincing (general population)Convincing (general population) inhibitors of adiponectin expression and secretion elevated levels of TNF-a seem to promote nearly all (ref. 139). Generally, adiponectin is acknowledged to steps leading to cancer, from cellular transformation be anti-inflammatory and antiatherogenic (140-143), and to metastasis (Table 4; refs. 114, 151, 152). Because TNF-a lower levels of adiponectin are strongly associated with mRNA and TNF-a protein are released by adipose tis- insulin resistance (144, 145), perhaps more strongly than sue (153-155), weight loss may decrease circulating obesity or adiposity (146).
Although lower levels of adiponectin may imply To our knowledge, only one epidemiologic study has increased risk for postmenopausal breast cancer, we evaluated TNF-a in postmenopausal breast cancer (ref.
found only a possible association based on our literature 156; Table 2). This cohort study followed 2,438 older review (Table 2). Five of seven studies in postmenopaus- adults (ages 70-79 years) for an average of 5.5 years.
al women showed negative associations, but none Despite biological plausibility, no association was found were prospective in nature and therefore these data are between circulating TNF-a and breast cancer incidence.
limited for assessing causality. In relation to physical Similarly, of four studies investigating physical activity activity, only a hypothesized association exists at this and TNF-a (128, 129, 157, 158), none found a statistically time (Table 3). We identified only two studies of exercise significant association, although lower TNF-a levels and adiponectin in postmenopausal women (129, 147); corresponded with increased physical activity in one both were prospective trials, but neither found any study (cross-sectional; ref. 157) and TNF-a levels statistically significant effect.
decreased after 14 weeks of exercise in another (RCT; The effect of exercise on adiponectin in other pop- ref. 129). Consequently, we classified both associations as ulations (i.e., not exclusively postmenopausal women) hypothesized (Tables 2 and 3).
has been reviewed previously (148, 149). Despite three of IL-6. IL-6 is a cytokine that occurs predominantly in eight exercise trials producing significantly increased circulating form (159) originating from a number of adiponectin levels in one review (148), the overall sources (160) including fibroblasts, macrophages, lym- evidence on chronic exercise was inconclusive because phocytes (145), skeletal muscle (161), and adipose tissue many factors were uncontrolled for, namely, weight (162). Obesity is strongly associated with elevated change, diet, and the effects of cytokines. Further- circulating IL-6 (161), although it is estimated that more, regression analysis of 15 exercise trials found no adipocytes per se account for only 10% of IL-6 released significant relation between changes in body weight and from adipose tissue (163). Because TNF-a stimulates the adiponectin (148). According to another review (149), release of IL-6, it is suggested that moderate increases in chronic exercise that improves fitness, increases insulin systemic IL-6 and CRP may actually reflect chronic sensitivity, and reduces body weight will increase TNF-a production (164, 165). IL-6 has a broad range adiponectin levels if the training volume is sufficiently of regulatory functions involving inflammation and high and lasts longer than 2 months. Whether exercise immune responses (15) but might also increase breast influenced adiponectin through weight loss alone was cancer risk by IL-6 – induced insulin resistance (145) and unclear from these studies (149).
aromatase activity (Table 4; ref. 166).
TNF-a. TNF-a is a cytokine produced mainly by Our review identified only one study examining IL-6 macrophages that infiltrate adipose tissue in obesity levels relative to postmenopausal breast cancer risk; no (109) but also by a variety of tumor cells, including breast significant association was found (156) and so we carcinoma (114, 150). TNF-a is well known for its critical deemed this association hypothesized (Table 2). Interest- roles in host defense, inflammation, and organogenesis ingly, other studies not exclusive to postmenopausal (151). The relation of TNF-a to cancer, however, is less women have showed higher IL-6 levels in breast cancer straightforward. Although TNF-a can induce apoptosis cases relative to controls (167-171), and some have and necrosis, as its name implies, chronic moderately implicated IL-6 as a negative prognosticator in breast Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Physical Activity and Postmenopausal Breast Cancer Table 4. Possible mechanisms relating recently proposed biomarkers to postmenopausal breast cancer risk andphysical activity Proposed Biomarker Possible role in postmenopausal breast cancer Possible impact of physical activity inpostmenopausal women Induces aromatase and stabilizes estrogen Weight loss decreases body fat, which is the main receptor-a (57, 122, 124, 266-268).
source of circulating leptin (122-124).
Although leptin can improve insulin sensitivity (145), elevated leptin levels are associatedwith insulin resistance (117). Hypothalamicactions of leptin could theoretically decreasesystemic insulin sensitivity and adiponectinproduction (269).
Expression is induced by high levels of estrogens and insulin (124, 141, 268).
Mitogen in breast cancer cells (15); inhibits apoptosis; pro-angiogenic (111, 122, 124, 141).
Gene expression and secretion from adipocytes are Fat loss decreases IL-6 and TNF-a (138), which are reduced by TNF-a and IL-6 (57, 142); production potent inhibitors of adiponectin expression and might also be reduced partially by leptin (269).
secretion (139). Hence, weight loss may increase Promotes and enhances insulin sensitivity circulating adiponectin levels. Chronic physical (140, 142, 144, 270); reduced adiponectin leads activity may lower inflammation (e.g., circulating to insulin resistance and compensatory IL-6, TNF-a) independently of fat loss (118); however, the mechanisms for this effect Antiangiogenic (272); antimitogenic, and anti- are unknown.
inflammatory (111). In one breast cancer cell lineadiponectin had no effect on apoptosis but didinhibit cell proliferation (273).
A key regulator of IL-6 synthesis (57).
Fat loss may decrease TNF-a levels given that TNF-a Stimulates estrogen biosynthesis via aromatase mRNA and TNF-a protein are released from induction (166).
adipose tissue in obesity (153-155).
Induces insulin resistance (109, 164).
Chronic physical activity may reduce the number Paradoxical action: inhibits tumor cell proliferation of mononuclear cells in the blood thereby depleting (274) but also acts as a tumor promoter a source of TNF-a (138).
(151, 152, 275). Can cause direct DNA damage;antiapoptotic and mitogenic (151); promotes invasion,angiogenesis and metastasis of tumor cells(114, 150, 152).
Release is stimulated by TNF-a; has been speculated Although the acute effects of exercise on IL-6 levels that systemic IL-6 reflects ongoing production of have been studied widely (160), the mechanisms TNF-a (164, 165); IL-6 in turn, exerts inhibitory whereby chronic physical activity alter IL-6 levels effects on TNF-a (165).
are unclear (161).
Plays a primary role in stimulating hepatic Reduced adiposity may decrease IL-6 levels given production of CRP (159).
that IL-6 originates from adipose tissue (162), among Produces insulin resistance in adipocytes (276, 277); other sources.
possible role in type 2 diabetes (160).
Chronic physical activity may reduce the number Stimulates estrogen biosynthesis by the induction of of mononuclear cells in the blood thereby depleting aromatase activity (166).
a source of IL-6 (138).
Promotes breast cancer cell motility suggesting a role in metastasis (167).
Complex role of IL-6 in breast cancer cells in vitro.
Up-regulates antiapoptotic and angiogenic proteinsin tumor cells but also induces apoptosis inestrogen receptor – positive mammary carcinomacell lines (172).
A prototypical marker of inflammation (174).
Long-term physical activity may decrease CRP by Production is promoted by TNF-a and IL-6 (112).
reducing adiposity, by reducing cytokine production Independently associated with leptin in healthy (i.e., IL-6 and TNF-a) in muscle and mononuclear individuals, possibly via induction of IL-6 by cells, or by other means (179).
leptin (278).
CRP production is strongly, positively related to insulin resistance and can change with insulinlevels independently of changes in obesity (279).
cancer patients (172). Therefore, a similar relation in weight loss can reduce IL-6 (138), exercise might modify postmenopausal women remains plausible.
IL-6 levels through an independent mechanism.
We classified the relation between physical activity and IL-6 in postmenopausal women as hypothesized CRP. CRP is a hepatocyte-derived, acute phase protein (Table 3). Only cross-sectional studies were identified, considered to be the prototypical marker of inflammation and two (157, 173) of the three showed significant inverse in humans (174) and might also affect postmenopausal associations. In both studies, statistical significance was breast cancer risk. CRP levels correlate positively with maintained even after adjusting for BMI. Thus, although weight (175, 176) and weight gain (177) and have been Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Cancer Epidemiology, Biomarkers & Prevention similarly related to type 2 diabetes risk (178). Because the highest versus the lowest physical activity levels physical activity confers benefits in each of these (179). In another review, longitudinal studies showed conditions, one might expect it similarly to decrease reduced CRP levels with exercise training (180).
In postmenopausal women it remains unclear whether We identified only two studies of CRP levels and exercise or weight loss modifies CRP levels (119, 138).
postmenopausal breast cancer risk. Due to the limited One review concluded that CRP levels decline whether epidemiologic literature, we deemed the association to be weight loss is achieved through exercise or diet (181), hypothesized (Table 2). It is noteworthy, however, that implying weight loss is most important. A meta-analysis both were cohort studies and neither found a statistically of five RCTs of long-term exercise training in men and significant association. In contrast, an association be- women found statistically significant decreases in body tween CRP and physical activity has been more widely weight and adiposity but only a nonsignificant reduc- studied and is quite persuasive (Table 3). We identified tion in CRP levels, suggesting neither exercise nor four studies in postmenopausal women, including one weight loss is effective (182); however, not all subjects prospective trial and one RCT; all four found that higher had high CRP levels at baseline and only one study levels of physical activity corresponded to lower levels of focused on postmenopausal women (183). In the latter circulating CRP. We regarded this association as con- RCT of breast cancer survivors, the mean CRP level vincing in postmenopausal women. Reviews in other decreased in the exercise group, but relative to controlsthis decrease was not statistically significant ( populations support this conclusion. One review of 17 cross-sectional studies of regular physical activity Proposed Biological Model. An overview of our pro- showed consistent evidence of lowered serum CRP in posed mechanisms for breast cancer (Tables 1 and 4) and Figure 1. Biological model relating proposed biomarkers to long-term exercise (shading) and postmenopausal breast cancer risk(arrows).
Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Physical Activity and Postmenopausal Breast Cancer a summary of findings from our literature review (Tables 2 Therefore, the effect of exercise could be entirely or only and 3) are illustrated in Fig. 1. This figure suggests that partially dependent on weight loss. The available the co-occurrence of overweight/obesity, insulin resis- literature does not adequately address whether fitness tance, and chronic inflammation may increase postme- or decreased fatness is more important for lowering nopausal breast cancer risk through several complex postmenopausal breast cancer risk. However, the Nutri- biological mechanisms. As shown, the most convinc- tion and Exercise in Women (NEW) Trial led by Dr. Anne ing epidemiologic evidence supports associations between McTiernan will address this issue in an ongoing RCT breast cancer risk and body weight, estrogens, and andro- involving over 500 postmenopausal women (13). Addi- gens, respectively. In relation to physical activity, asso- tionally, Holt et al. (185) recently explored the effect of fit ciations were most convincing for body weight, estrone, versus fat on insulin sensitivity in a study of 25 men. The leptin, insulin resistance, and CRP levels. Only body independent effects of adiposity, physical fitness, and weight and estrone were convincingly (or probably) physical activity energy expenditure were compared.
associated with breast cancer risk and physical activity.
Multiple regression analysis revealed significant rela- The least amount of evidence supported roles for TNF-a tions between adiposity and whole body insulin sensi- and IL-6 in this model based on the epidemiologic tivity, and between physical activity energy expenditure evidence to date.
and liver insulin sensitivity. We encourage similar This review focused on postmenopausal women and studies in the future, designed specifically to compare thus, we can only speculate on the effects of these the effects of physical activity and weight loss and to influences over the life course. Hypothetically, cumula- measure biomarkers prospectively during interventions.
tive lifetime levels of some biomarkers (e.g., related to The generalizability of our model is tempered by insulin resistance or inflammation) might affect post- potential effect modification. It is possible, for instance, menopausal breast cancer risk, and sustained physical that the proposed mechanisms contribute only in certain activity could modify lifetime exposure. However, the high-risk subgroups of postmenopausal women (e.g., epidemiologic evidence relating physical activity and obese women with BMI z30 and/or insulin resistance) body size to breast cancer is less convincing for for whom, according to our model, exercise might confer premenopausal women (4, 5, 184) and hence, the the greatest benefits. Additional factors such as genetic proposed biological model probably becomes more polymorphisms, family history, race, diet, and medica- important after menopause. This finding might reflect a tions might further modify the roles of the proposed bio- mechanism involving adiposity and sex hormones, for markers on breast cancer risk. For example, weight gain example, because only after menopause, when ovarian and BMI only increase postmenopausal breast cancer production of estrogens has ceased, does adipose tissue risk in never users of hormone replacement therapy become the primary source of circulating estrogens.
(186-191). The effect of exercise on breast cancer risk maybe similarly modified by hormone replacement therapyuse. Two (192, 193) of at least four (192-195) observa- Discussion and Future Research Directions tional studies that examined effect modification of thiskind found a stronger protective effect of physical activity This review provides an overview of three commonly among never hormone replacement therapy users as com- proposed mechanisms relating physical activity to pared with ever users. Furthermore, one cross-sectional postmenopausal breast cancer risk; namely overweight study of postmenopausal women showed a two-fold and obesity, insulin resistance, and chronic inflamma- increased median CRP level in hormone replacement tion. As illustrated in our model, several mechanisms therapy users compared with nonusers with control for potentially act simultaneously to increase postmeno- potential confounders (196). Besides hormone replace- pausal breast cancer risk with opposing, promoting, and ment therapy, several other CRP-altering medications possibly synergistic pathways at play. Considering the have been identified (197). Finally, dietary composition complexity of the model, it is not surprising that and smoking could hypothetically modify the benefits of epidemiologic findings have been inconsistent for some exercise by influencing insulin resistance and inflamma- candidate biomarkers. Several questions remain regard- tion (198-200). Given the multitude of potential effect ing the biological mechanisms that mediate the associa- modifiers in our model, the notion that physical activity tion between physical activity and breast cancer. Which decreases breast cancer risk generally in postmenopausal biomarkers are most predictive of risk? Which are direct women cannot be practically applied to individuals.
versus indirect consequences of exercise? The proposed It is also conceivable that the proposed biomarkers model also has important implications for the design and increase risk for only certain tumor types; namely, analysis of future etiologic studies. It is conceivable, for hormone receptor – positive or hormone receptor – neg- instance, that the combined effects of elevated sex ative tumors. Interactions with estrogen receptor status hormones, insulin resistance, and elevated inflammatory have been explored previously, for instance, in relation markers present greater risk than any one factor to breast cancer risk and body weight (186, 191, 201), individually; future etiologic studies should explore adiposity (202), sex hormone levels (203), impaired potential interactions among biomarkers. The notion that glucose metabolism (99), serum adiponectin (204), and interacting pathways connect physical activity to breast IL-6 levels (171). Furthermore, a recent review provided cancer risk was proposed by Hoffman-Goetz et al. ten preliminary evidence that physical activity produces a years ago (10), but since then most epidemiologic somewhat greater risk reduction for hormone recep- researchers have continued to study candidate bio- tor – negative tumors (estrogen receptor negative/pro- markers in isolation.
gesterone receptor negative) than for hormone As shown in our model, all of the proposed bio- receptor – positive tumors (estrogen receptor positive/ markers are, at least indirectly, related to body size.
progesterone receptor positive; ref. 6). Future etiologic Cancer Epidemiol Biomarkers Prev 2009;18(1). January 2009 Cancer Epidemiology, Biomarkers & Prevention studies should similarly consider tumor characteristics positive associations with circulating insulin (213) and to advance the interpretation of our model.
CRP levels (214) in postmenopausal women.
Despite the potential importance of frequency, dura- Positive associations have been found in many, but not tion, or intensity, surprisingly little evidence exists for all, studies of waist-hip ratio, waist circumference, or defining an effective exercise prescription to reduce other measures of central adiposity and breast cancer risk postmenopausal breast cancer risk (4). One might expect in postmenopausal women (3, 32, 33, 36, 75). Abdominal particular types of physical activity to target abdominal fatness was deemed a probable risk factor for postmen- fat and perhaps greater levels of energy expenditure to opausal breast cancer in the World Cancer Research achieve greater weight loss. Some authors propose that Fund/American Institute for Cancer Research 2007 exercise of greater duration, intensity, or volume may report (4). However, current North American guidelines also be most effective for decreasing leptin (130, 131) and claim there is only limited evidence supporting the increasing adiponection (149). Hence, it would be very effectiveness of physical activity for abdominal fat loss useful for future exercise intervention trials to compare (ref. 40; also concluded by ref. 215) and only modest the effects of different exercise prescriptions in the reductions in abdominal fat to be expected, if at all (39).
context of our biological model.
It remains plausible, however, that postmenopausal Our review revealed several noteworthy gaps in past women could be amenable to significant abdominal fat epidemiologic research. First, there is clearly a lack of loss given the most effective exercise prescription (e.g., prospective exercise trials examining sex hormone evidenced by refs. 17, 108, 216). Thus, further exercise changes in postmenopausal women undergoing physical trials and etiologic studies are needed, ideally using activity modification. Thus, it is unclear whether or not more accurate measures of abdominal fat such as dual exercise is causal in reducing androgen and estrogen energy X-ray absorptiometry. Perhaps more accurate, levels. This is important to note because sex hormones targeted anthropometric measures will clarify the role of are currently the most compelling candidate biomarkers, central adiposity.
given their probable/convincing associations with breast Our model focuses primarily on mechanisms related cancer risk (Table 2). Second, the biomarkers designated to the promotion of postmenopausal breast cancer, but as hypothesized in this review are hypothetical due physical activity could influence risk at several points largely to a lack of research. Only one study on TNF-a along the cancer continuum (8). Markers associated with and IL-6 (156) and two on CRP (156, 205) related detoxification pathways, DNA repair mechanisms, oxi- specifically to postmenopausal breast cancer risk. Fur- dative stress, and various aspects of immune function thermore, the soluble receptor for IL-6 (sIL-6R) is a could all be relevant to postmenopausal breast cancer known agonist of IL-6 activity whereas higher levels of and also modifiable by exercise (6, 8-10). Moreover, TNF soluble receptors (sTNFR1, sTNFR2) inhibit TNF-a recently proposed biomarkers may be integrated into our activity (206); these could additionally contribute to our model as new research is conducted. For example, proposed model. Therefore, in the context of postmen- resistin is an adipose tissue – derived polypeptide asso- opausal breast cancer, more epidemiologic research into ciated with (and named for) insulin resistance in rodents, inflammatory markers and their soluble receptors is but its role in humans remains controversial; it might induce insulin resistance or could play a proinflamma- Despite biological plausibility, our review of four tory role (217, 218). Resistin is an emerging risk factor for independent studies (128, 129, 157, 158) suggested no breast cancer with significantly increased serum levels in relation between TNF-a and physical activity level postmenopausal cases relative to controls in two recent (128, 129, 157, 158). This finding may indicate that studies (125, 219). However, two recent studies sug- greater levels of concurrent weight loss (or weight gested resistin is not modifiable by exercise (129, 220).
disparities in observational studies) are required before Still, based on the limited evidence to date, more research differences in TNF-a levels are detectable. Alternatively, is warranted to elucidate resistin's response to exercise changes in TNF-a might be confounded by dietary and its possible role in postmenopausal breast cancer.
composition, which is also associated with chronic In summary, the current review provides a conceptual inflammation (200). Finally, it is possible that compensa- framework for future research into the biological tory mechanisms to proinflammatory factors or perhaps mechanisms surrounding physical activity and postmen- soluble TNF receptors varied with exercise, but these opausal breast cancer risk. BMI and sex hormones have factors were not studied and/or were excluded from our so far been the most commonly cited biomarkers relat- review. Given these possibilities, excluding TNF-a from ing physical activity to decreased risk, but emerging evi- our model at this stage might be premature.
dence now suggests that insulin resistance and chronic To maximize the pool of literature for review, we inflammation could play pivotal roles. The important selected BMI and body weight as our surrogate interrelations between these mechanisms must be con- measures of adiposity. BMI predicts total body fat with sidered when analyzing data or planning future studies.
varying accuracy depending on the study population Two general types of prospective studies are required (207, 208) but is generally comparable with alternative to validate our model: cohort studies relating the pro- measures (BMI – % body fat, r = 0.69-0.75 (208, 209) and posed biomarkers to cancer risk, and exercise RCTs r = 0.81 for postmenopausal women (210); BMI – comparing biomarker changes at several time points over abdominal fat assessed by computer tomography, r = 0.8 the long term, specifically in postmenopausal women.
ref. 207). Therefore, BMI is an acceptable measure for Convincing findings from both fields of study, with guiding public health recommendations. Abdominal fat, account for effect modification, would strengthen the however, may be more etiologically relevant to breast existing epidemiologic evidence, and would ultimately cancer mechanistic research given its inverse association guide breast cancer prevention strategies for postmeno- with SHBG levels (211) and insulin sensitivity (212) and pausal women.
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KEEP OUT OF REACH OF CHILDREN READ SAFETY DIRECTIONS BEFORE OPENING OR USING TMENT ONLY TOR™ ACTIVE CONSTITUENT: 36.0 g/L ALBENDAZOLE OXIDE (equivalent to 34.0 g/L ALBENDAZOLE) 82.5 g/L LEVAMISOLE HYDROCHLORIDE (equivalent to 70.0 g/L LEVAMISOLE) 1 g/L SELENIUM as SODIUM SELENATE For the control of gastrointestinal roundworms, sensitive to benzimidazoles and levamisole including those resistant

Eligability criteria

Assisted Conception Policy NHS Eligibility Criteria for assisted conception services (excluding In vitro fertilisation (IVF) Intracytoplasmic sperm injection (ICSI) treatment) for people with infertility in Nottinghamshire County. February 2011 Although Primary Care Trusts (PCTs) and East Midlands Specialised Commissioning Group (EMSCG) were abolished at the end of March 2013 with the formation of 5 Nottinghamshire County wide clinical Commissioning Groups (CCGs) policies that were in place prior to 1 April 2013 remain in place to ensure a consistent approach. The NHS Nottingham North & East Clinical Commissioning Group have adopted this policy, in its existing form, at a meeting of its Governing Body on 20 August 2013. This policy sets the overall parameters within which care will be delivered.