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Background: The optimal lifestyle for breast cancer prevention over the long term is unclear. We aimed to determine whether or not the amount of exercise prescribed in a year-long exercise intervention influences breast cancer biomarker levels 1 year later. Methods: We conducted a 24-month follow-up study (2012–2014) to the Breast Cancer and Exercise Trial in Alberta (BETA), a 12-month, two-armed (1:1), two-center randomized controlled trial of exercise in 400 cancer-free, postmenopausal women. The exercise prescription was moderate–vigorous aerobic exercise, 5 days/week (3 days/week supervised) for 30 minutes/session (MODERATE) or 60 minutes/session (HIGH). Participants were asked not to change their usual diet. We used linear mixed models to compare biomarker concentrations (C-reactive protein, insulin, glucose, HOMA-IR, estrone, sex hormone binding globulin, total estradiol, and free estradiol) over time (0, 12, and 24 months) by group (MODERATE, HIGH), using group–time interactions. Results: After 12 months of no intervention, 24-month fasting blood samples were available for 84.0% and 82.5% of MODERATE and HIGH groups, respectively (n = 333/400). We found no evidence that 0 to 24– or 12 to 24–month biomarker changes differed significantly between randomized groups (HIGH:MODERATE ratio of mean biomarker change ranged from 0.97 to 1.06, P values >0.05 for all). We found more favorable biomarker profiles among participants who experienced greater than the median fat loss during the trial. Conclusions: Prescribing aerobic exercise for 300 versus 150 minutes/week for 12 months to inactive, postmenopausal women had no effects on longer-term biomarkers. Impact: Exercise may lead to larger improvements in breast cancer biomarkers after intervention among women who also experience fat loss with exercise.

Background: Testicular germ cell tumor (TGCT) incidence has increased over the last 40 years in the United States. In contrast to TGCT among infants, it is hypothesized that TGCT in adolescents and young men is the result of sex steroid hormone imbalance during early fetal development. However, little is known about the neonatal period when abrupt hormonal changes occur, and direct supporting evidence is scarce due to the difficulties in obtaining prediagnostic specimens. Methods: We conducted a population-based case–control study examining hormone levels at birth among 91 infants (0–4 years) and 276 adolescents (15–19 years) diagnosed with TGCT, and 344 matched controls. Estrogen and androgen levels were quantified using liquid chromatography–tandem mass spectrometry (LC–MS/MS) from archived newborn dried blood spots. Logistic regression models were used to estimate the association between each hormone level and TGCT risk. Results: Higher levels of androstenedione were associated with increased TGCT risk among adolescents [odds ratio (OR): 2.33, 95% confidence interval (CI): 1.37–3.97 for highest vs. lowest quartile; P trend = 0.003] but not among infants (OR: 0.70, 95% CI: 0.28–1.77). A similar pattern was observed for testosterone (OR: 1.73, 95% CI: 1.00–3.00,) although the trend was not significant (P trend = 0.12). Associations were stronger among non-Hispanic white subjects, relative to Hispanics. There was no difference by tumor histologic subtype. Estriol (the only detectable estrogen) was not associated with TGCT risk in either age group. Conclusions: Higher levels of neonatal androgens were associated with increased risk of TGCT among adolescents, suggesting that early life hormone levels are related to the later development of TGCT. Impact: This is the first study with direct measures of sex steroid hormones to examine the relationship between estrogens and androgens at birth and risk of adolescent TGCT. Cancer Epidemiol Biomarkers Prev; 27(4); 488–95. ©2018 AACR.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.

Background: Breast density is a strong risk factor for breast cancer and reflects epithelial and stromal content. Breast tissue is particularly sensitive to hormonal stimuli before it fully differentiates following the first full-term pregnancy. Few studies have examined associations between sex hormones and breast density among young women. Methods: We conducted a cross-sectional study among 180 women ages 25 to 29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-up Study. Eighty-five percent of participants attended a clinic visit during their luteal phase of menstrual cycle. Magnetic resonance imaging measured the percentage of dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute nondense breast volume (ANDBV). Multiple-linear mixed-effect regression models were used to evaluate the association of sex hormones and sex hormone–binding globulin (SHBG) with %DBV, ADBV, and ANDBV. Results: Testosterone was significantly positively associated with %DBV and ADBV. The multivariable geometric mean of %DBV and ADBV across testosterone quartiles increased from 16.5% to 20.3% and from 68.6 to 82.3 cm3, respectively (Ptrend ≤ 0.03). There was no association of %DBV or ADBV with estrogens, progesterone, non–SHBG-bound testosterone, or SHBG (Ptrend ≥ 0.27). Neither sex hormones nor SHBG was associated with ANDBV except progesterone; however, the progesterone result was nonsignificant in analysis restricted to women in the luteal phase. Conclusions: These findings suggest a modest positive association between testosterone and breast density in young women. Impact: Hormonal influences at critical periods may contribute to morphologic differences in the breast associated with breast cancer risk later in life. Cancer Epidemiol Biomarkers Prev; 24(2); 369–78. ©2014 AACR.

Background: Results from prospective studies on the association between urinary levels of melatonin and risk of postmenopausal breast cancer have been mixed. Several although not all studies have found lower urinary levels of melatonin in women who developed breast cancer compared with cancer-free women. Methods: We examined the association between urinary levels of melatonin and breast cancer risk in postmenopausal women in a case–control study nested in the Women's Health Initiative Observational Cohort. Levels of 6-sulfatoxymelatonin were measured in first morning voids from 258 women who later developed breast cancer and from 515 matched controls. Multivariable conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI). Results: Fully adjusted risk estimates of breast cancer, relative to the lowest quartile level of creatinine-adjusted melatonin, were 1.07 (95% CI, 0.67–1.71), 1.26 (95% CI, 0.79–2.01), and 1.25 (95% CI, 0.78–2.02) for women in the second, third, and highest quartile (Ptrend = 0.27). Comparable results for cases diagnosed less than four years after urinary collection and matched controls were 1.0, 1.25 (95% CI, 0.51–3.06), 1.85 (95% CI, 0.75–4.57), and 1.94 (95% CI, 0.75–5.03; Ptrend = 0.11). Melatonin levels and breast cancer were not associated in cases diagnosed four or more years after urinary collection and matched controls (Ptrend = 0.89). Conclusions: We found no evidence that higher urinary levels of melatonin are inversely associated with breast cancer risk in postmenopausal women. Impact: Accumulating discrepancies in results across studies warrant further exploration. Cancer Epidemiol Biomarkers Prev; 23(4); 629–37. ©2014 AACR.

Background: Finasteride, an inhibitor of 5α-reductase (type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG). It also modestly increases serum testosterone (T), estrone (E1), and estradiol (E2). In this altered hormonal milieu, it is unknown whether serum concentrations of these hormones are associated with prostate cancer risk. Methods: In this nested case–control study of men in the finasteride arm of the Prostate Cancer Prevention Trial, sex steroid hormones and sex hormone binding globulin were measured at baseline and approximately 3-year posttreatment in 553 prostate cancer cases and 694 controls. Results: Median posttreatment changes in concentrations of 3α-dG, T, E1, and E2 were −73.8%, +10.1%, +11.2%, and +7.5% (all P < 0.001), respectively. Neither the pre- nor posttreatment concentrations of 3α-dG, nor its change, were associated with risk. Pretreatment, high concentrations of E1 and low concentrations of T were associated with increased cancer risk [OR; 95% confidence interval (CI) quartile 4 vs. 1: 1.38 (0.99–1.93) Ptrend = 0.03; 0.64 (0.43–0.93) Ptrend = 0.07, respectively]. Posttreatment, high concentrations of both E1 and E2 were associated with increased cancer risk [OR; 95% CI quartile 4 vs. 1: 1.54 (1.09–2.17) Ptrend = 0.03; 1.49 (1.07–2.07) Ptrend = 0.02, respectively]. Conclusions: Among finasteride-treated men, concentrations of 3α-dG were not associated with total or Gleason grades 2 to 6, 7 to 10, or 8 to 10 cancer. High serum estrogens may increase cancer risk when intraprostatic DHT is pharmacologically lowered. Impact: Low posttreatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer. Cancer Epidemiol Biomarkers Prev; 21(10); 1823–32. ©2012 AACR.

Background: On the basis of hypothesized protective effect, we examined the effect of soy foods on estrogens in nipple aspirate fluid (NAF) and serum, possible indicators of breast cancer risk. Methods: In a crossover design, we randomized 96 women who produced 10 μL or more NAF to a high- or low-soy diet for 6 months. During the high-soy diet, participants consumed 2 soy servings of soy milk, tofu, or soy nuts (∼50 mg of isoflavones per day); during the low-soy diet, they maintained their usual diet. Six NAF samples were obtained using a FirstCyte aspirator. Estradiol (E2) and estrone sulfate (E1S) were assessed in NAF and estrone (E1) in serum only, using highly sensitive radioimmunoassays. Mixed-effects regression models accounting for repeated measures and left-censoring limits were applied. Results: Mean E2 and E1S were lower during the high-soy than the low-soy diet (113 vs. 313 pg/mL and 46 vs. 68 ng/mL, respectively) without reaching significance (P = 0.07); the interaction between group and diet was not significant. There was no effect of the soy treatment on serum levels of E2 (P = 0.76), E1 (P = 0.86), or E1S (P = 0.56). Within individuals, NAF and serum levels of E2 (rs = 0.37; P < 0.001) but not of E1S (rs = 0.004; P = 0.97) were correlated. E2 and E1S in NAF and serum were strongly associated (rs = 0.78 and rs = 0.48; P < 0.001). Conclusion: Soy foods in amounts consumed by Asians did not significantly modify estrogen levels in NAF and serum. Impact: The trend toward lower estrogen levels in NAF during the high-soy diet counters concerns about adverse effects of soy foods on breast cancer risk. Cancer Epidemiol Biomarkers Prev; 20(9); 1815–21. ©2011 AACR.

Background: Inflammation is hypothesized to play a role in colorectal tumorigenesis. Circulating levels of C-reactive protein (CRP), a serologic marker of the inflammatory response, have been positively associated with colorectal cancer development in some studies; however, there are limited data on the relation of CRP with colorectal adenomas, established precursors of colorectal cancer. Methods: A nested case–control investigation of CRP levels and incident colorectal adenoma was conducted in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a randomized trial of 154,942 individuals designed to test the efficacy of flexible sigmoidoscopy on colorectal cancer mortality when performed once, and then repeated 3 to 5 years later. Serum CRP levels were measured in baseline blood specimens from participants who were free of polyps in the left-sided colorectum at the baseline screening procedure, but who were found at the subsequent screen to have at least one colorectal adenoma (n = 356), and in a set of polyp-free, frequency-matched controls (n = 396). Results: In a multivariable logistic regression model that included established colorectal adenoma risk factors, a 1-unit increase in log CRP level was associated with a 15% reduction in risk of developing colorectal adenoma (OR = 0.85, 95% CI, 0.75–0.98, Ptrend = 0.01). This association did not differ according to body size, smoking behavior, gender, use of nonsteroidal antiinflammatory drugs, or adenoma location. Conclusions: High circulating CRP levels may be protective against colorectal adenoma development. Impact: Though at contrast with mechanistic data on inflammation and colorectal tumorigenesis, this finding is not inconsistent with prior results on CRP and colorectal adenoma and warrants further investigation. Cancer Epidemiol Biomarkers Prev; 20(3); 537–44. ©2011 AACR.

The incidence of breast cancer in the U.S. varies by race/ethnicity. Furthermore, in Hispanic women, breast cancer risk is higher among women with low Indigenous American ancestry compared to those with high Indigenous American ancestry and in U.S.-born compared to foreign-born women. In a previous pilot study among foreign-born and U.S.-born Mexican women, we found that plasma estrogenic (E) activity was associated with genetic ancestry and years of U.S. residence, suggesting the possibility of a hormone-related pathway for the observed differences in breast cancer risk. In the present study, we examined the association between E activity and genetic ancestry in a larger sample of Hispanic women. We also evaluated the association between E activity, demographic factors, and breast cancer risk in non-Hispanic Black (NHB) and non-Hispanic White (NHW) women. We utilized a receptor-mediated Chemical-Activated Luciferase gene eXpression (CALUX) assay for the assessment of total activity profiles against estrogen receptors (ER) in human plasma, which captures levels of both endogenous and exogenous estrogenic compounds. Results were expressed in relative light units (RLUs), with higher RLU values reflecting greater E activity in plasma. ER activation was measured in plasma samples of 329 Hispanic, 100 NHBs, and 74 NHW women who participated as controls in the San Francisco Bay Area Breast Cancer Study (SFBCS). The participants ranged in age from 35 to 79 years, though the study was composed predominantly of postmenopausal women. Multivariable regression models included race/ethnicity, age at blood draw, height, body mass index (BMI), neighborhood socioeconomic status (SES), and alcohol intake. In the univariate model that included all women (n=503) and race/ethnicity as the independent predictor, Hispanics had 24% lower E activity (p=0.061) and NHBs had 36% higher activity (p=0.047) compared to NHWs. In the multivariable model, Hispanics still showed lower E activity levels (34%, p=0.009), but the difference with NHBs and NHWs was no longer statistically significant (p=0.493). After adjustment for levels of two endogenous estrogens, estradiol and estrone, in a subset of samples (n=260), Hispanics continued to show 20% lower E activity compared to NHWs. In addition, when BMI is categorized into tertiles consisting of normal (30 kg/m2) women, we found that obese women had 73% higher E activity compared to those with normal BMI (p Citation Format: Sylvia S. Sanchez, Phum Tachachartvanich, Heather Ruiz, Frank Z. Stanczyk, Scarlett Lin Gomez, Esther M. John, Martyn T. Smith, Laura Fejerman. Estrogenic activity is associated with race/ethnicity and Indigenous American ancestry among San Francisco Bay Area women [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr PR05.

Background: Adolescent diet is hypothesized to influence breast cancer risk. We evaluated the long-term effects of an intervention to lower fat intake among adolescent girls on biomarkers that are related to breast cancer risk in adults. Methods: A follow-up study was conducted on 230 girls who participated in the Dietary Intervention Study in Children (DISC), in which healthy, prepubertal, 8 to 10 year olds were randomly assigned to usual care or to a behavioral intervention that promoted a reduced fat diet. Participants were 25 to 29 years old at follow-up visits. All tests of statistical significance are two-sided. Results: In analyses that did not take account of diet at the time of the follow-up visit, the only statistically significant treatment group difference was higher bone mineral content in intervention group participants compared with usual care group participants; their mean bone mineral contents were 2,444 and 2,377 g, respectively. After adjustment for current diet, the intervention group also had statistically significantly higher bone mineral density and luteal phase serum estradiol concentrations. Serum progesterone concentrations and breast density did not differ by treatment group in unadjusted or adjusted analyses. Conclusions: Results do not support the hypothesis that consumption of a lower fat diet during adolescence reduces breast cancer risk via effects on subsequent serum estradiol and progesterone levels, breast density, or bone mineral density. It remains unclear, however, if the results are specific to the DISC intervention or are more broadly applicable. Impact: Modest reductions in fat intake during adolescence are unlikely to lower later breast cancer risk via long-term effects on the biomarkers measured. Cancer Epidemiol Biomarkers Prev; 19(6); 1545–56. ©2010 AACR.

Epidemiologic studies fairly consistently show in postmenopausal women that reproductive steroid hormones contribute to primary breast cancer risk, and this association is strongly supported by experimental studies using laboratory animals and model systems. Evidence linking sex hormone concentrations with risk for recurrence in women diagnosed with breast cancer is limited; however, beneficial effects of antiestrogenic therapy on recurrence-free survival suggest that these hormones affect progression and risk for recurrence. This study examined whether baseline serum concentrations of estradiol, testosterone, and sex hormone binding globulin were associated with recurrence-free survival in a nested case-control cohort of women from a randomized diet trial (Women's Healthy Eating and Living Study) who were followed for >7 years after diagnosis. In 153 case-control pairs of perimenopausal and postmenopausal women in this analysis, total estradiol [hazard ratio (HR), 1.41 per unit increase in log concentration; 95% confidence interval (95% CI), 1.01-1.97], bioavailable estradiol (HR, 1.26; 95% CI, 1.03-1.53), and free estradiol (HR, 1.31; 95% CI, 1.03-1.65) concentrations were significantly associated with risk for recurrence. Recurred women had an average total estradiol concentration that was double that of nonrecurred women (22.7 versus 10.8 pg/mL; P = 0.05). Testosterone and sex hormone binding globulin concentrations did not differ between cases and controls and were not associated with risk for recurrence. Although genetic and metabolic factors likely modulate the relationship between circulating sex hormones and risk, results from this study provide evidence that higher serum estrogen concentration contributes to risk for recurrence in women diagnosed with early stage breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(3):614–20)

Naturopathic physicians commonly make dietary and/or dietary supplement recommendations for breast cancer prevention. This placebo-controlled, parallel-arm, pilot study tested the effects of two naturopathic interventions over five menstrual cycles on sex steroid hormones and metabolic markers in 40 healthy premenopausal women. The intervention arms were as follows: combination botanical supplement (Curcuma longa, Cynara scolymus, Rosmarinus officinalis, Schisandra chinensis, Silybum marinum, and Taraxacum officinalis; n = 15), dietary changes (3 servings/d crucifers or dark leafy greens, 30 g/d fiber, 1-2 liters/d water, and limiting caffeine and alcohol consumption to 1 serving each/wk; n = 10), and placebo (n = 15). Early-and late-follicular phase serum samples from cycles 1 and 5 were analyzed for estrogens (estrone, estrone-sulfate, total estradiol, and free estradiol), androgens (dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, total testosterone, and free testosterone), sex hormone-binding globulin, and metabolic markers (insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and leptin). Serum samples collected during the mid-luteal phase of cycles 1 and 5 were analyzed for total estradiol, free estradiol, and sex hormone-binding globulin. Urine samples collected during the late follicular phase of cycles 1 and 5 were analyzed for 2-hydroxyestrone and 16α-hydroxyestrone. During the early follicular phase, compared with placebo, the botanical supplement decreased dehydroepiandrosterone (−13.2%; P = 0.02), dehydroepiandrosterone-sulfate (−14.6%; P = 0.07), androstenedione (−8.6%; P = 0.05), and estrone-sulfate (−12.0%; P = 0.08). No other trends or statistically significant changes were observed. When comparing dietary changes with placebo, no statistically significant differences were observed. Overall, in this pilot study, the naturopathic interventions had no substantial effects on estrogen measures. Early-follicular phase androgens decreased with the botanical supplement. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1601–9)

There is an increasing trend to apply gas chromatography combined with mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) assay methods to large-scale epidemiologic studies for the measurement of serum sex steroids. These methods are generally considered the gold standard for sex steroid measurements because of their accuracy, sensitivity, turnaround time, and ability to assess a more complete panel of steroid metabolites in the same run. In this report, we evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility, of steroid hormone measurements determined by GC-MS and LC-MS/MS assays and RIA and compared measurements among these methods. Specifically, 282 overnight fasting serum samples from 20 male volunteers were analyzed for 12 steroid metabolites by GC-MS or LC-MS/MS in one lab over a 4-month period. Six of the analytes were also measured by RIA in another lab. Unconjugated hormones, including testosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione, androst-5-ene-3β,17β-diol, estrone, and estradiol, were measured by GC-MS, whereas conjugated hormones, including DHEA sulfate, androsterone glucuronide, 5α-androstane-3α,17β-diol 3-glucuronide, 5α-androstane-3α,17β-diol 17-glucuronide, and estrone sulfate, were measured by LC-MS/MS. A subset of these hormones, including testosterone, dihydrotestosterone, androstenedione, 5α-androstane-3α,17β-diol 17-glucuronide, estrone, and estradiol, were also measured by RIA following extraction and chromatography. We used the coefficient of variation (CV) and the intraclass correlation coefficient (ICC) to assess within- and between-batch assay variations. For the 12 analytes measured by GC-MS or LC-MS/MS, CVs and ICCs for within- and between-batch measurements were similar, with CVs ranging from 6.1% to 21.4% and ICCs ranging from 87.6% to 99.2%. The six analytes measured by RIA had good CVs and ICCs, with CVs 70% (range, 71.7-99.7%). For the six metabolites that were measured by both methods, the CVs were similar, whereas the ICCs were generally higher with the GC-MS method. The absolute values for each analyte measured by RIA and GC-MS differed, with RIAs usually yielding markedly higher levels than GC-MS, although the Pearson and Spearman correlation coefficients for these six analytes were near one and all were significant (P < 0.001). Our results show that RIA, GC-MS, and LC-MS/MS assays for androgens and estrogens in the two labs included in the study have good reproducibility, as measured by small CVs (80%), with the exception of estradiol (71.7%) when measured by RIA. Despite substantial differences in absolute measurements of sex steroid hormones by RIA and MS methods, correlations between the two assays for the six sex steroids measured in the two labs were high (>0.9). However, it is important for future large epidemiologic studies to incorporate MS with high reproducibility and specificity to measure a more complete profile of androgen and estrogen metabolites to clarify the role of sex steroids in prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(5):1004–8)

Postmenopausal women with increased estrogens and lowered sex hormone–binding globulin (SHBG) concentrations are at increased risk of breast cancer. In the Multiethnic Cohort Study, the highest incidence rates of postmenopausal breast cancer were observed among Native Hawaiians followed by Japanese Americans, Whites, African Americans, and Latinas. Ethnic differences in endogenous sex hormone profiles may contribute to some of the variation in breast cancer incidence. Plasma concentrations of androstenedione, testosterone, estrone (E1), estradiol (E2), and SHBG were measured in 739 postmenopausal women from the Multiethnic Cohort Study (240 African Americans, 81 Native Hawaiians, 96 Japanese Americans, 231 Latinas, and 91 Whites). After adjusting for age, known breast cancer risk factors and lifestyle factors, the mean levels of testosterone, estrogen, and SHBG varied across populations (Ps ≤ 0.004). Across racial/ethnic groups, Native Hawaiians had the highest mean levels of androstenedione, testosterone, and estrogens and the lowest mean levels of SHBG. Compared with Whites, Native Hawaiians had higher androstenedione (+22%, P = 0.017), total testosterone (+26%, P = 0.013), bioavailable testosterone (+33%, P = 0.002), E1 (≥21%; P = 0.009), total E2 (+26%, P = 0.001), bioavailable E2 (+31%, P < 0.001), and lower SHBG (−12% P = 0.07) levels. Compared with Whites, Japanese Americans had higher E2 (+15%, P = 0.036) and bioavailable E2 (+18%, P = 0.024) levels. African Americans also had higher E1 (+21%, P = 0.004), E2 (+20%, P = 0.007), and bioavailable E2 (+20%, P = 0.015) levels compared with Whites, whereas mean levels in Latinas were similar to those of Whites. Many of the differences in endogenous postmenopausal hormonal milieu across these five racial/ethnic groups are consistent with the known differences in breast cancer incidence across these populations. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1849–55)

Cryptorchism is one of the few well-described risk factors for testicular cancer. It has been suggested that both conditions are related to increased in utero estrogen exposure. The evidence supporting the “estrogen hypothesis” has been inconsistent, however. An alternative hypothesis suggests that higher in utero androgen exposure may protect against the development of cryptorchism and testicular cancer. In order to examine both hypotheses, we studied maternal hormone levels in two populations at diverse risks of testicular cancer; Black Americans (low-risk) and White Americans (high-risk). The study population of 200 mothers of cryptorchid sons and 200 mothers of noncryptorchid sons was nested within the Collaborative Perinatal Project, a cohort study of pregnant women and their children. Third trimester serum levels of estradiol (total, free, bioavailable), estriol, testosterone (total, free, bioavailable), sex hormone–binding globulin, α-fetoprotein, and the ratios of estradiols to testosterones were compared between the case and control mothers. The results found no significant differences in the levels of testosterone (total, free, bioavailable), α-fetoprotein, sex hormone–binding globulin, or in the ratios of estrogens to androgens. Total estradiol, however, was significantly lower in the cases versus the controls (P = 0.03) among all mothers and, separately, among White mothers (P = 0.05). Similarly, estriol was significantly lower among all cases (P = 0.05) and among White cases (P = 0.05). These results do not support either the estrogen or the androgen hypothesis. Rather, lower estrogens in case mothers may indicate that a placental defect increases the risk of cryptorchism and, possibly, testicular cancer.

There is evidence that circulating estrogens are associated with breast cancer risk. In this study of premenopausal women, we explored the association of polymorphisms in genes in the estrogen synthesis and metabolism pathways with serum and urinary levels of estrone (E1) and estradiol (E2) and with the urinary ratio of 2-hydroxyestrone (2-OHE1)/16α-hydroxyestrone (16α-OHE1). This analysis included 220 women, who were participants in a 2-year randomized soy intervention. Blood specimens were collected in the luteal phase of the menstrual cycle an average of 4.4 times over 2 years. Overnight urinary specimens were collected on the same cycle day, only at baseline. Levels of E1, E2, 2-OHE1, and 16α-OHE1 were measured by enzyme immunoassays. The DNA samples were analyzed by PCR/RFLP for the COMT Val158Met, CYP1A1*2A, CYP1A1*2B, CYP1A2*1F, CYP1B1 Val432Leu, and CYP17 T27C polymorphisms. We applied mixed models to investigate the relations between genotypes and repeated serum hormone measurements and generalized linear models to assess associations between genotypes and urinary estrogen metabolites. The CYP1A2 C allele was significantly associated with lower serum E2 levels; in CC genotype carriers, serum E2 levels were 26.3% lower than in homo- and heterozygous common allele carriers combined (P = 0.01). CYP1A2*1F also affected the urinary 2-OHE1/16α-OHE1 ratio; carriers of the variant C allele had a markedly lower ratio than individuals with the AA genotype (1.37 versus 1.76; P = 0.002). These data suggest that CYP1A2*1F is associated with lower circulating levels of E2, and that it may be a susceptibility locus for breast cancer.

Objective: Hormone therapy use has been positively associated with mammographic density in several studies. However, few studies have examined the association between endogenous hormone levels and mammographic density. Therefore, we evaluated the relationship of endogenous sex hormones, insulin-like growth factor (IGF), and lipids with mammographic density in 88 overweight, postmenopausal women not taking hormone therapy. Methods: Percent density and dense area were evaluated as continuous measures using a computer-assisted program. We used multiple linear regression to evaluate the associations of sex hormones, IGF, and cholesterol with mammographic density, adjusting for confounders, including adiposity. We evaluated stratification by history of hormone therapy use (former versus never) and hormone therapy latency ( Results: Among former hormone therapy users, mammographic density was inversely associated with circulating levels of estrone (P = 0.01), estradiol (P = 0.003), free estradiol (P = 0.004), testosterone (P = 0.04), free testosterone (P = 0.02), androstenedione (P < 0.001), dehydroepiandrosterone (P = 0.01), and the ratio of IGF-I to its binding protein (IGF-I/IGFBP-3; P = 0.04). We found similar associations when we limited the analyses to women who had used hormone therapy within the past 5 years. We also noted positive associations of mammographic density with total cholesterol (P = 0.03) and low-density lipoprotein (P = 0.03) among former hormone therapy users. No associations were noted among women who had never used hormone therapy. Conclusions: These results suggest that there is an inverse relationship between endogenous sex hormones and mammographic density in postmenopausal women among former users of hormone therapy. This is not consistent with the hormone therapy literature and should be confirmed in larger studies.

Objective: Several epidemiologic studies have described protective effects of soy consumption against breast cancer. The goal of this trial among premenopausal women was to examine the effect of soy foods on menstrual cycle length and circulating sex hormone levels. Methods: This 2-year dietary intervention randomized 220 healthy premenopausal women. The intervention group consumed two daily servings of soy foods containing ∼50 mg of isoflavones; the control group maintained their regular diet. Five blood samples (obtained in months 0, 3, 6, 12, and 24) were taken 5 days after ovulation as determined by an ovulation kit. The serum samples were analyzed for estrone, estradiol, sex hormone binding globulin, androstenedione, and progesterone by immunoassay. Results: At baseline, both groups had similar demographic, anthropometric, and nutritional characteristics. The dropout rates of 15.6% (17 of 109) in the intervention group and 12.6% (14 of 111) in the control group did not differ significantly. According to soy intake logs, 24-hour recalls, and urinary isoflavone excretion, the women closely adhered to the study regimen. Menstrual cycles became slightly shorter in both groups but did not differ by group. Mixed general linear models indicated no significant intervention effect on any of the serum hormones. However, androstenedione and progesterone decreased significantly over time in both groups. Conclusions: The results of this study suggest that the preventive effects of soy on breast cancer risk in premenopausal women may not be mediated by circulating sex hormone levels. Different mechanisms of actions or effects of exposure earlier in life are alternate hypotheses that require further investigation.

Postmenopausal women with elevated circulating androgen concentrations have an increased risk of developing breast cancer, yet interventions to reduce androgen levels have not been identified. We examined the effects of a 12-month moderate intensity exercise intervention on serum androgens. The study was a randomized clinical trial in 173 sedentary, overweight (body mass index ≥ 24.0 kg/m2, body fat > 33%), postmenopausal women, ages 50 to 75 years, not using hormone therapy and living in the Seattle, WA area. The exercise intervention included facility-based and home-based exercise (45 minutes, 5 days per week of moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study, with exercisers averaging 171 minutes per week of exercise. Women in the exercise and control groups experienced similar, nonsignificant declines in most androgens. Among women who lost >2% body fat, testosterone and free testosterone concentrations fell by 10.1% and 12.2% between baseline and 12 months in exercisers compared with a decrease of 1.6% and 8.0% in controls (P = 0.02 and 0.03 compared with exercisers, respectively). Concentrations of testosterone and free testosterone among exercisers who lost between 0.5% and 2% body fat declined by 4.7% and 10.4%. In controls who lost this amount of body fat, concentrations of testosterone and free testosterone declined by only 2.8% and 4.3% (P = 0.03 and 0.01 compared with exercisers, respectively). In summary, given similar levels of body fat loss, women randomized to a 12-month exercise intervention had greater declines in testosterone and free testosterone compared with controls. The association between exercise and breast cancer risk may be partly explained by the effects of exercise on these hormones.

A meta-analysis indicated that increased circulating concentrations of insulin-like growth factor 1 (IGF-1) are associated with increased risks for colorectal, prostate, and premenopausal breast cancers, and that increased concentrations of IGF binding protein 3 (IGFBP-3) are associated with