Circulating Hormones and Mammographic Density in Premenopausal Women

Prior research suggests that several endogenous hormones in premenopausal women are associated with breast cancer risk; however, few studies have evaluated associations of endogenous hormones with mammographic density (MD) in premenopausal women. We conducted a cross-sectional study of plasma hormone levels in relation to MD among 634 cancer-free premenopausal women in the Nurses’ Health Study II. We measured percent MD from screening mammograms using a computer-assisted method. We assayed estradiol, estrone, and estrone sulfate in blood samples timed in early follicular and mid-luteal phases of the menstrual cycle as well as testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, sex hormone–binding globulin (SHBG), and anti-Müllerian hormone in luteal or untimed samples. We used multivariable linear regression to quantify the association of %MD with quartiles of each hormone, adjusting for age, body mass index, and breast cancer risk factors. Women in the highest quartile of follicular estradiol levels had significantly greater %MD compared to those in the lowest quartile [difference, 6.7 percentage points; 95% confidence interval (CI) 2.2, 11.3; p-trend?<?0.001]. Similar associations were observed for follicular free estradiol but not luteal-phase estradiol. Also, women in the top (vs. bottom) quartile of free testosterone had significantly lower %MD (difference, ??4.7; 95% CI ??8.7, ??0.8; p-trend?=?0.04). Higher SHBG was significantly associated with higher percent MD (difference, 4.8; 95% CI 1.1, 8.6; p-trend?=?0.002). Percent MD was not strongly associated with other measured hormones. Results were similar in analyses that excluded women with anovulatory cycles. Our findings suggest that follicular estradiol and SHBG may play an important role in premenopausal percent MD.     

Serum levels of sex hormones and breast cancer risk in premenopausal women: a case–control study (USA)

High levels of serum estrogens and androgens have been convincingly linked with an increased risk of breast cancer among postmenopausal women. By contrast, the role of blood levels of these hormones in the etiology of premenopausal breast cancer is not well understood. In a case-control study, we sought to examine associations between levels of serum estradiol, sex-hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), testosterone, androstenedione and progesterone and risk of premenopausal breast cancer. Cases of breast cancer under age 45 were identified using rapid ascertainment systems in Seattle/Puget Sound, Washington and control subjects were identified from the same area through random digit dialing methods. A total of 169 eligible breast cancer cases and 195 control subjects donated blood (either before or six or more weeks after surgery) and were interviewed using a standardized questionnaire. The fully adjusted risk ratios and 95% confidence intervals for the highest versus lowest tertiles of estradiol, according to menstrual cycle phase, were 3.10 (0.8-12.7) for early follicular, 0.54 (0.2-1.7) for late follicular and 0.60 (0.3-1.4) for luteal. Risks for highest versus lowest quartiles of SHBG and androgens were 0.81 (0.4-1.6) for SHBG, 2.42 (1.1-5.2) for DHEA, 1.12 (0.6-2.5) for testosterone, and 1.33 (0.6-2.8) for androstenedione. For luteal progesterone, the RR for the highest versus lowest tertile was 0.55 (0.2-1.4). In summary, we did not find a convincing association between serum SHBG, estradiol, testosterone or androstenedione and premenopausal breast cancer risk. Observed differences between cases and controls subjects in serum levels of DHEA and luteal phase progesterone should be investigated further in large prospective studies.     

Physical activity and inactivity in relation to sex hormone,prolactin, and insulin-like growth factor concentrations in premenopausal women

An association between physical activity and premenopausal breast cancer risk may be due, in part, to relationships with sex hormones or growth factors. Therefore, we assessed whether MET-h/week of total physical activity (moderate-to-vigorous intensity), walking, or vigorous physical activity, and h/week of standing or sitting were associated with plasma concentrations of several hormones. We examined levels of estrogens, androgens, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and growth hormone (GH) in 565 premenopausal women, ages 33–52 years, from the Nurses’ Health Study II (NHSII). About 87% of women had both timed follicular and luteal samples; other women had one untimed sample. In general we observed few associations between sex hormone or IGF levels and measures of physical activity or inactivity. However, free testosterone was modestly inversely associated with total physical activity (p-trend = 0.02). Luteal estradiol, free estradiol, and estrone also were inversely associated with total physical activity (p-trend = 0.10, 0.04, 0.01, respectively); however, the trend was substantially attenuated when excluding women with anovulatory cycles or irregular cycles. These cross-sectional results suggest that physical activity and inactivity have limited associations with premenopausal sex hormone and growth factor levels, except possibly luteal estrogens. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Support for this project was from NIH grants CA67262, CA50385, P50 CA089393, and DAMD-17-02-1-0692. Dr. Eliassen was supported by Cancer Education and Career Development Grant R25 CA 098566-2 from the National Cancer Institute.     

Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women

BACKGROUND:

Circulating estrogens and androgens are important factors in the development of various female cancers. Caffeine intake may decrease risk of breast and ovarian cancer, although the data are not entirely consistent. Whether or not caffeine affects cancer risk by altering sex hormone levels is currently unknown.

METHODS:

We examined the relationship of caffeine, coffee, decaffeinated coffee, and tea with plasma concentrations of estrogens, androgens, progesterone, prolactin, and sex hormone–binding globulin (SHBG) in 524 premenopausal and 713 postmenopausal women from the Nurses' Health Study (NHS) and NHSII.

RESULTS:

In premenopausal women, caffeine intake was inversely associated with luteal total and free estradiol, and positively associated with luteal progesterone levels (P‐trend = .02, .01, .03, respectively). Coffee intake was significantly associated with lower luteal total and free estradiol levels, but not luteal progesterone levels (P‐trend = .007, .004, .20, respectively). Among the postmenopausal women, there was a positive association between caffeine and coffee intake and SHBG levels (P‐trend = .03 and .06, respectively). No significant associations were detected with the other hormones.

CONCLUSIONS:

Data from this cross‐sectional study suggest that caffeine may alter circulating levels of luteal estrogens and SHBG, representing possible mechanisms by which coffee or caffeine may be associated with pre‐ and postmenopausal malignancies, respectively. Future studies evaluating how caffeine‐mediated alterations in sex hormones and binding protein levels affect the risk of female cancers are warranted. Cancer 2009. © 2009 American Cancer Society.     

Associations between endogenous sex hormone levels and mammographic and bone densities in premenopausal women

Purpose  Mammographic breast and bone mineral densities (BMD) have been associated with luteal phase hormone concentrations in premenopausal women. We assessed the associations of breast and bone densities with follicular phase hormones and sex hormone binding globulin (SHBG) in premenopausal women, given that follicular phase hormones have been shown to be positively associated with premenopausal breast cancer risk. Methods  One hundred and ninety-two 40–45-year-old women provided a spot urine and/or blood sample during the follicular phase. Hormone and SHBG concentrations, and bone density were measured and routine mammograms were accessed and digitized to obtain breast density measures. Regression models were fit to assess the associations between hormones and SHBG, and breast and bone densities. Results  Positive associations were observed between percent breast density and SHBG (p trend = 0.02), as well as estradiol (p trend = 0.08), after controlling for body mass index (BMI), number of pregnancies, and breast feeding history. In addition, a statistically significant inverse association was observed between total testosterone and head BMD (p trend = 0.01), after controlling for BMI. Conclusions  Associations were observed between breast and bone densities, and serum hormone concentrations during the follicular phase of the menstrual cycle.     

Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide

Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.     

Menstrual cycle characteristics and steroid hormone,prolactin, and growth factor levels in premenopausal women

Purpose

Menstrual cycle characteristics are markers of endocrine milieu. However, associations between age at menarche and adulthood sex steroid hormone levels have been inconsistent, and data on menstrual characteristics and non-sex steroid hormones are sparse.

Methods

We assessed the relations of menstrual characteristics with premenopausal plasma sex steroid hormones, sex hormone binding globulin (SHBG), prolactin, and growth factors among 2,745 premenopausal women (age 32–52) from the Nurses’ Health Study II. Geometric means and tests for trend were calculated using multivariable general linear models.

Results

Early age at menarche was associated with higher premenopausal early-follicular free estradiol (percent difference <?12 vs.?>?13 years?=?11%), early-follicular estrone (7%), luteal estrone (7%), and free testosterone (8%) (all p _trend?<?0.05). Short menstrual cycle length at age 18–22 was associated with higher early-follicular total (<?26 vs.?>?39 days?=?18%) and free estradiol (16%), early-follicular estrone (9%), SHBG (7%), lower luteal free estradiol (??14%), total (??6%), and free testosterone (??15%) (all p _trend?<?0.05). Short adult menstrual length was associated with higher early-follicular total estradiol (<?26 vs.?>?31 days?=?14%), SHBG (10%), lower luteal estrone (??8%), progesterone (??9%), total (??11%) and free testosterone (??25%), and androstenedione (??14%) (all p _trend?<?0.05). Irregularity of menses at 18–22 was associated with lower early-follicular total (irregular vs. very regular?=???14%) and free estradiol (??14%), and early-follicular estrone (??8%) (All p _trend?<?0.05). Irregularity of adult menstrual cycle was associated with lower luteal total estradiol (irregular vs. very regular?=???8%), SHBG (??3%), higher total (8%), and free testosterone (11%) (all p _trend?<?0.05).

Conclusions

Early-life and adulthood menstrual characteristics are moderately associated with mid-to-late reproductive year’s hormone concentrations. These relations of menstrual characteristics with endogenous hormone levels could partially account for associations between menstrual characteristics and reproductive cancers or other chronic diseases.

     

Reproducibility of plasma steroid hormones, prolactin, and insulin-like growth factor levels among premenopausal women over a 2- to 3-year period.

Few studies have evaluated whether a single blood hormone measurement, as is available in most epidemiologic studies, sufficiently characterizes a premenopausal woman's long-term hormone levels; there is particular concern whether sex steroid hormones, which fluctuate during the menstrual cycle, are reliable. We conducted a prospective study within the Nurses' Health Study II to examine the reproducibility of plasma estrogens, androgens, progesterone, prolactin, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3). One blood sample per year over 3 years was collected from 113 premenopausal women during both the follicular and luteal phases of the menstrual cycle. We calculated intraclass correlation coefficients (ICC) across the three samples for all women. Among estrogens, ICCs ranged from 0.38 (estradiol) to 0.60 (estrone sulfate) in the follicular phase and from 0.44 (estrone) to 0.69 (estrone sulfate) in the luteal phase. Among androgens, ICCs ranged from 0.58 (androstenedione) to 0.94 [dehydroepiandrostenedione sulfate (DHEAS)] in the follicular phase and from 0.56 (testosterone) to 0.81 (DHEAS) in the luteal phase. When values were averaged across the follicular and luteal phases, the ICC for prolactin was 0.64 whereas ICCs for IGF-I and IGFBP-3 were 0.86 and 0.82, respectively. The ICC for progesterone in the luteal phase was only 0.29. These data suggest that for androgens, estrone sulfate, prolactin, IGF-I, and IGFBP-3, a single measurement can reliably categorize average levels over at least a 3-year period in premenopausal women. For estrone and estradiol, where ICCs were relatively low, it is important to use reproducibility data such as those to correct for measurement error in epidemiologic studies.     

Associations of alcohol, height, and reproductive factors with serum hormone concentrations in postmenopausal Japanese women

We measured serum levels of estradiol (E₂), sex hormone-binding globulin (SHBG), progesterone, and dehydroepiandrosterone sulfate (DHEAS) in 61 postmenopausal women drawn from female residents in a community in Japan to evaluate the relationships between these hormone levels and potential breast cancer risk factors. The information on reproductive history, body size, alcohol use, and physical activity was obtained by means of a self-administered questionnaire. There was a significant trend in increasing E₂ level with increasing height after taking account of age and body mass index (BMI) (p for trend = 0.04). BMI was inversely associated with SHBG level after controlling for age (p for trend = 0.01). Decreasing progesterone with increasing BMI was observed after controlling age and history of hysterectomy (P=0.05). Alcohol consumption was positively associated with E₂ level and there was a strong linear trend after controlling for age, height, and BMI (p for trend=0.001). Trend for increasing DHEAS with alcohol consumption was also statistically significant after controlling for age and history of hysterectomy (p for trend=0.01). Reproductive factors as well as physical activity were not related to any of the hormone levels.     

Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses' Health Study II

Introduction

Prior research supports an association between endogenous sex steroids and breast cancer among postmenopausal women; the association is less clear among premenopausal women.

Methods

We evaluated the associations between estrogens, androgens, progesterone and sex hormone binding globulin (SHBG) and breast cancer in a nested case-control study in the Nurses'' Health Study II. Between 1996 and 1999, 29,611 participants provided blood samples; 18,521 provided samples timed in early follicular and mid-luteal phases of the menstrual cycle. A total of 634 women, premenopausal at blood collection, developed breast cancer between 1999 and 2009 and were matched to 1,264 controls (514 cases and 1,030 controls with timed samples). We used conditional logistic regression controlling for breast cancer risk factors for overall analyses; unconditional logistic regression additionally controlling for matching factors was used for subgroup analyses.

Results

In analyses of premenopausal estrogens including breast cancers diagnosed both before and after menopause, there was no association between follicular estradiol, estrone and free estradiol and risk of either total or invasive breast cancer. Luteal estradiol was positively associated with estrogen receptor positive (ER+)/progesterone receptor positive (PR+) cancers (5^th vs. 1^st quintile odds ratio (OR): 1.7 (95% confidence interval (CI): 1.0 to 2.9), P_trend = 0.02). Luteal estrone, free estradiol and progesterone were not associated with risk. Androgens were suggestively or significantly associated with risk when the sample was restricted to invasive tumors (for example, testosterone: OR: 1.4 (1.0 to 2.0), P_trend = 0.23) and ER+/PR+ disease (testosterone: OR: 1.7 (1.1 to 2.6) P_trend = 0.10; dehydroepiandrosterone sulfate (DHEAS) OR: 1.3 (0.8 to 2.0) P_trend = 0.05). SHBG was not associated with breast cancer risk. The results varied by menopausal status at diagnosis, with follicular estradiol suggestively positively associated with breast cancers in women premenopausal at diagnosis (OR: 1.1 (0.9 to 1.3) and significantly inversely associated with postmenopausal disease (OR: 0.6 (0.4 to 0.9); P_{heterogeneity} < 0.01).

Conclusions

Androgens were associated with modestly increased risk of breast cancer in this population, with stronger associations for invasive and ER+/PR+ disease. Luteal phase estradiol levels were suggestively associated with ER+/PR+ tumors but no other strong associations were observed with estrogens. Associations with follicular phase estrogens may vary by menopausal status at diagnosis, but case numbers were limited. Additional studies to confirm the role of premenopausal hormones in the etiology of both premenopausal and postmenopausal breast cancer are needed.     

Does the increase of endogenous steroid hormone levels also affect breast cancer risk in Chinese women? A case–control study in Chongqing,China

Accumulating epidemiological evidence suggests that sex steroid hormones are positively associated with the development of breast cancer. However, most of these studies were conducted among Caucasian women and few have been carried out in China. To determine whether the associations of sex steroid hormone levels with breast cancer risk observed by and large in Caucasian populations are also evident in Chinese women, we conducted a case–control study in Chongqing, China. The study included 367 incident breast cancer patients and 367 healthy controls matched on menstrual status, age and periods of blood collection in the menstrual cycle. Plasma concentrations of estradiol, progesterone, testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were determined by electrochemiluminescene immunoassay (ECLIA). Conditional logistic regression analysis was performed to examine their associations with breast cancer risk. From comparisons of upper and lower tertiles, we observed statistically significant positive associations with breast cancer risk for plasma estradiol levels in follicular phase (adjusted odds ratio [OR] = 5.48, 95% confidence interval [CI] = 1.58–18.97), luteal phase (OR = 4.23, CI = 1.65–10.87) and postmenopausal (OR = 2.67, CI = 1.20–5.93); for progesterone levels in luteal phase (OR = 3.11, CI = 1.28–7.56), and for testosterone levels in postmenopausal (OR = 2.83, CI = 1.26–6.35). No significant association was found with DHEAS or SHBG. Our study suggests that high circulating levels of estradiol and testosterone are positively associated with increased breast cancer risk in Chinese women, which are generally consistent with the observations in Caucasian populations. © 2008 Wiley‐Liss, Inc.     

Usual physical activity and endogenous sex hormones in postmenopausal women: the European prospective investigation into cancer-norfolk population study.

BACKGROUND: Short-term trials indicate that intensive physical activity may influence endogenous sex hormone concentrations. However, the relationship between usual daily physical activity and endogenous hormones in postmenopausal women in the general population is still uncertain. OBJECTIVE AND METHODS: To determine the relationship between usual physical activity and endogenous sex hormones in postmenopausal women. A cross-sectional population-based study of 2,082 postmenopausal women ages 55 to 81 years, residing in the general community of Norfolk, United Kingdom, and not currently using hormone replacement therapy were chosen to participate. Physical activity in the past 1 year was assessed using a validated questionnaire, and endogenous sex hormone and sex hormone-binding globulin (SHBG) concentrations were determined. RESULTS: Usual physical activity levels were inversely associated with circulating concentrations of testosterone and estradiol, testosterone/SHBG ratio, and positively associated with SHBG. These associations were only slightly attenuated after adjusting for potential covariates including body mass index, smoking status, alcohol intake, and reproductive variables. Testosterone concentrations and testosterone/SHBG ratios were 19% [95% confidence interval (95% CI), 9-27%, P < 0.001] and 24.0% (95% CI, 13-34% P < 0.001) lower, respectively, whereas estradiol concentrations were 6% (95% CI, 0-12%; P < 0.05) lower in the highest compared with lowest activity levels, respectively. A decreasing trend for the estradiol/SHBG ratio and 17alpha-hydroxyprogesterone concentrations was also observed. Androstenedione levels did not differ significantly according to physical activity. CONCLUSIONS: Higher usual physical activity levels among postmenopausal women seem to be related to lower endogenous testosterone and estradiol concentrations. This may be one mechanism that could partly explain the reported inverse relationship between physical activity and breast cancer risk in some studies.     

The relation of reported alcohol ingestion to plasma levels of estrogens and androgens in premenopausal women (Maryland,United States)

We undertook a cross-sectional study in 107 premenopausal women in Maryland (United States) of alcohol intake and hormonal status in order to evaluate whether plasma hormone levels might mediate the reported positive relation between alcohol ingestion and breast cancer risk. Alcohol ingestion was estimated using a drinking pattern questionnaire, a food frequency questionnaire, and seven-day food records. Fasting blood specimens were collected on days 5–7, 12–15, and 21–23 of each participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Estrone, estrone sulfate, estradiol, androstenedione, and dehydropiandrosterone sulfate (DHEAS) in plasma were measured by radioimmunoassay, and sex-hormone binding globulin (SHBG) was measured by an immunoradiometric assay. After adjusting for age, weight, and total energy intake, alcohol ingestion was not associated with plasma estrogens in the follicular, midcycle, or luteal phases of the menstrual cycle, nor with the level of SHBG or DHEAS in plasma averaged from the three phases of the cycle. Alcohol, however, was significantly positively associated with the average level of plasma androstenedione. Based on these cross-sectional findings among premenopausal women, the increased risk of breast cancer related to alcohol ingestion does not appear to be mediated by elevated plasma estrogen levels. Androstenedione, however, may mediate the alcohol/breast cancer-association.Division of Cancer Prevention and Control     

Body size and composition,physical activity and sedentary time in relation to endogenous hormones in premenopausal and postmenopausal women: Findings from the UK Biobank

Anthropometric and lifestyle factors may influence cancer risks through hormonal changes. We investigated cross-sectional associations between body size and composition, physical activity and sedentary time and serum concentrations of oestradiol (premenopausal women only), testosterone, sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I) in 20 758 premenopausal and 71 101 postmenopausal women in UK Biobank. In premenopausal women, higher BMI (body mass index) was associated with a lower concentration of total oestradiol (15% difference in the highest vs lowest BMI group) and a higher concentration of calculated free oestradiol (22%). In both premenopausal and postmenopausal women, higher BMI was associated with higher concentrations of total and calculated free testosterone (premenopausal 29% and 113%, postmenopausal 39% and 126%, respectively) and lower concentrations of SHBG and IGF-I (premenopausal 51% and 14%, postmenopausal 51% and 12%, respectively). Similar associations were observed with waist to height ratio, waist to hip ratio and body or trunk fat mass. Self-reported physical activity was associated with somewhat lower concentrations of total and calculated free testosterone (premenopausal 10% difference [free testosterone], postmenopausal 5% and 11% difference respectively in the most vs least active group) and a higher concentration of SHBG (premenopausal 11%, postmenopausal 10%), and the opposite was true for self-reported sedentary time. The associations were slightly stronger with accelerometer-measured physical activity, but were attenuated after adjustment for BMI. Overall, our study confirms strong associations of hormones and SHBG with anthropometric factors. The associations with physical activity and sedentary time were at most modest.     

Serum hormone levels in relation to reproductive and lifestyle factors in postmenopausal women (United States)

Objectives: Endogenous sex hormones are thought to be involved in breast and endometrial cancers, but few studies have evaluated the relationships between hormones and risk factors for these diseases. Methods: We related serum hormone and sex-hormone binding globulin (SHBG) levels to reproductive and lifestyle risk factors in a cross-sectional study of 125 postmenopausal women in five geographic regions of the United States. Results: The estrogens were associated positively, while SHBG was associated negatively with body mass index (wt/ht 2). Estrone, (E1), estrone sulfate, and bioavailable estradiol (BioE2) were inversely associated with height. Androstenedione was positively associated with age at menopause, while androstenedione, E1, estradiol, and BioE2 were inversely associated with age at menarche. Weekly alcohol drinkers had higher hormone levels, and lower SHBG levels than those who abstained. Androstenedione and E1 decreased with increasing levels of nonrecreational activity. Conclusions: Several of these findings support the hypothesis that breast and endometrial cancer risk factors are mediated, in part, through increased endogenous hormone levels. The androstenedione findings are of interest in light of studies relating androstenedione to endometrial and possibly breast cancer. An association of age at menarche with E2, independent of androstenedione, may reflect increased aromatase activity in women with earlier menarche.     

Endogenous sex hormones and subsequent breast cancer in premenopausal women

Because of large intra-individual variation in hormone levels, few studies have investigated the relation of serum sex hormones to breast cancer (BC) in premenopausal women. We prospectively studied this relation, adjusting for timing of blood sampling within menstrual cycle. Premenopausal women (5,963), recruited to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study, provided a blood sample in the 20-24th day of their menstrual cycle. After 5.2 years of follow-up, 65 histologically confirmed BC cases were identified and matched individually to 4 randomly selected controls. Sera, stored at -80 degrees C, were assayed blindly for dehydroepiandrosterone sulfate, total and free testosterone (FT), androstenedione, androstanediol-glucoronide, progesterone, 17-OH-progesterone, sex hormone-binding globulin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fifty-five cases had information for multivariate analyses. Compared to controls, BC cases had shorter cycles and intervals between blood sampling and bleeding, and lower LH and FSH. FT was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women.     

Dietary patterns, the Alternate Healthy Eating Index and plasma sex hormone concentrations in postmenopausal women

To evaluate the association between overall diet and sex hormones concentrations, we collected blood from 578 postmenopausal women ages 43 and 69 years in 1989 or 1990. Food intake was measured in 1990 via a food frequency questionnaire. We calculated the Alternate Healthy Eating Index (AHEI), and dietary patterns were identified by factor analysis. The cross-sectional association between diet and estrogens, sex hormone binding globulin (SHBG) were evaluated with linear regression and adjusted for energy and other potential confounders. We found a higher AHEI score was associated with lower concentrations of estradiol, free estradiol, and higher concentrations of SHBG. The prudent pattern, with higher intakes of fruits, vegetables, and whole grains, was not associated with any sex hormones. The Western pattern, which represents higher intakes of red and processed meats, refined grains, sweets and desserts, was associated with a higher level of estradiol and lower concentrations of SHBG. Further adjustment for BMI attenuated these results except for free estradiol (5th vs. 1st quintile = 0.09 vs. 0.11 pg/mL, p for trend = 0.03). In addition, the AHEI was inversely associated with estradiol among those with BMI > 25, and Western pattern with SHBG among those with BMI < 25. In conclusion, we observed inverse associations between the AHEI score and several estrogens, and it was positively associated with plasma levels of SHBG. In contrast, the Western pattern was positively associated with estrogen levels and inversely with SHBG. However, these associations appeared to be largely accounted for by BMI.     

Physical activity, sex steroid, and growth factor concentrations in pre- and post-menopausal women: a cross-sectional study within the EPIC cohort

Purpose

Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations.

Methods

A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case–control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA.

Results

In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was <2 %.

Conclusions

Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.     

Relationship between serum hormone concentrations,reproductive history,alcohol consumption and genetic polymorphisms in pre-menopausal women

Reproductive characteristics, alcohol intake and polymorphisms in genes encoding sex-steroid metabolizing enzymes might influence the risk of hormone-related cancers by changing circulating concentrations of sex hormones. The relationship between these factors and serum concentrations of estradiol, progesterone, androstenedione, testosterone and DHEA was evaluated in a cross-sectional study of 218 pre-menopausal women from Kaiser Permanente Health Plan in Portland, Oregon. Risk factor information was obtained from questionnaires and hormone serum concentrations were determined by radioimmunoassays. Genotypes for CYP11A 5'UTR(tttta)n, CYP17 5'-UTR -34 T>C, CYP19 IVS4(ttta)n, CYP1B1 (L432V and S453N) and COMT (V158M) were determined from genomic DNA samples. Increasing number of full-term pregnancies was associated with a significant decrease in late-follicular progesterone levels (p-trend = 0.03). Increasing alcohol consumption was associated with higher estradiol levels averaged through the menstrual cycle (p-trend = 0.009) and higher progesterone levels during luteal phase (p-trend = 0.04). Androstenedione and testosterone levels were higher among light to moderate drinkers compared to non-drinkers, although we only observe a significant trend with increasing levels of alcohol consumption for androstenedione. Women heterozygous or homozygous for the CYP1B1 L432V or the S453N polymorphisms had increased luteal estradiol levels (p-value = 0.04 for L432V and 0.04 for S453N). None of the other factors evaluated was significantly associated with serum concentration of hormones. In conclusion, results from this cross-sectional study of pre-menopausal women provide support for an association between light to moderate alcohol intake and elevated levels of estrogen and androgen levels. Our data suggest that circulating levels of progesterone might be related to parity and alcohol consumption, however the biological plausibility of the observed associations is unclear. We found little support for an influence of the evaluated genetic polymorphisms in the steroid synthesis and metabolism pathway on serum hormone levels, except for a possible effect of the CYP1B1 L432V and S453N polymorphisms on serum estradiol levels.     

Adiposity and sex hormones in girls.

Greater body fatness during childhood is associated with reduced risk of premenopausal breast cancer, but few studies have addressed the relation of adiposity with sex hormones in girls. We prospectively examined associations between adiposity and circulating levels of sex hormones and sex hormone-binding globulin (SHBG) among 286 girls in the Dietary Intervention Study in Children. Participants were 8 to 10 years old at baseline and were followed for an average of 7 years. Anthropometric measurements were taken at baseline and at subsequent annual visits, and blood samples were collected every 2 years. Concentrations of dehydroepiandrosterone sulfate (DHEAS) during follow-up were higher among girls with greater body mass index (BMI) at baseline. The mean for the lowest BMI quartile was 63.0 microg/dL compared with 78.8 microg/dL for the highest quartile, and each kg/m(2) increment in baseline BMI was associated with a 4.3% increase (95% confidence interval, 1.6-7.0%) in DHEAS levels during follow-up (P(trend) = 0.002). Concentrations of SHBG during follow-up were lower among girls with greater BMI at baseline. The mean for the lowest BMI quartile was 94.8 nmol compared with 57.5 nmol for the highest quartile, and each kg/m(2) increment in baseline BMI was associated with an 8.8% decrease (95% confidence interval, 7.0-10.6%) in SHBG levels during follow-up (P(trend) < 0.0001). Estrogen and progesterone concentrations were similar across BMI quartiles. These findings suggest that adiposity may alter DHEAS and SHBG levels in girls. Whether and how these differences affect breast development and carcinogenesis requires further research.