Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96–2.92, p_trend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96–3.30, p_trend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28–1.05, p_trend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.     

Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study

Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case–control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (OR_T3-T1?=?1.59, 95 % CI?=?0.96, 2.64, p?=?0.08) and free testosterone (OR_T3-T1?=?1.76, 95 % CI?=?1.01, 3.07, p?=?0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n?=?51 cases; ≥55 years, n?=?110 cases). Among women who were ≥55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI?=?1.25, 3.44, p?=?0.005) for a doubling in testosterone and 1.55 (95 % CI?=?1.04, 2.31, p?=?0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged ≥55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted.     

Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up

Plasma estrogen and androgen levels are positively associated with postmenopausal breast cancer risk, but how long a single blood measurement can predict risk and whether the associations vary by tumor hormone receptor status remain unclear. We conducted nested case–control analyses within the Nurses’ Health Study. Blood samples were collected in 1989–1990 and again in 2000–2002. Among postmenopausal women not using postmenopausal hormones at blood collection, 707 cases were diagnosed through June 2010, with two matched controls per case. We used unconditional logistic regression analyses to estimate the relative risks controlling for other breast cancer risk factors. The intra-class correlation coefficients for two blood measurements collected 10 years apart ranged from 0.54 (dehydroepiandrosterone sulfate, DHEAS) to 0.74 (sex hormone-binding globulin, SHBG). Overall, women in the top (vs. bottom) 25 % of levels of estradiol, free estradiol, testosterone, free testosterone, and DHEAS were at a 50–110 % higher risk of breast cancer (p _trend < 0.001). SHBG was inversely associated with risk (p _trend = 0.004). RRs were similar when comparing cases diagnosed 1–10 versus 11–20 years (or 16–20 years) after blood collection (p _interaction > 0.2). Except for DHEAS, the associations varied significantly by hormone receptor status (p _{heterogeneity} ≤ 0.02). For example, the RRs (95 % CIs) comparing the highest versus lowest quartile were 2.8 (2.0–4.0; p _trend < 0.001) for ER +/PR + tumors versus 1.1 (0.6–2.1; p _trend = 0.98) for ER?/PR? tumors for estradiol, and 1.8 (1.3–2.5; p _trend < 0.001) versus 0.6 (0.3–1.2; p _trend = 0.35) for testosterone. One measure of circulating sex hormones in postmenopausal women can predict risk of hormone receptor positive breast cancer for up to 16–20 years.     

Endogenous sex hormones and colorectal cancer survival among men and women

Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone-binding globulin (SHBG) with CRC-specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC-specific deaths) in men and 106 deaths (70 CRC-specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45–0.99, p_trend = 0.04) and possibly CRC-specific mortality (HR = 0.73, 95% CI, 0.41–1.29, p_trend = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC-specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92–2.60, p_trend = 0.11) and CRC-specific mortality (HR = 1.96, 95% CI, 1.01–3.84, p_trend = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.     

Postmenopausal breast cancer risk in relation to sex steroid hormones, prolactin and SHBG (Sweden)

Objective: High levels of sex steroid hormones and prolactin have been suggested to enhance breast cancer development. Low levels of SHBG may indicate high levels of (bio-available) steroid hormones. The present study investigates whether high levels of sex steroid hormones and prolactin, and/or low levels of SHBG, are associated with high breast cancer risk. Methods: Blood samples were collected in about 65,000 women participating in two population-based prospective cohort studies in Sweden. Follow-up yielded 173 postmenopausal breast cancer cases who had not been exposed to HRT. Levels of estrone, estradiol, SHBG, FSH, prolactin, testosterone, androstenedione and DHEAs were analysed in cases and 438 controls. Logistic regression analysis yielded odds ratios (ORs), with 95% confidence intervals, adjusted for potential confounders. Results: The risk of breast cancer was associated with the highest versus lowest quartiles of estrone, OR: 2.58 (1.50–4.44), estradiol (dichotomised: high versus low) (1.73: 1.04–2.88), and testosterone (1.87: 1.08–3.25). High risks, although not statistically significant, were seen for androstenedione (1.58: 0.92–2.72) and DHEAs (1.62: 0.89–2.72). No strong associations were seen between SHBG or prolactin and risk of breast cancer. Conclusions: High levels of estrone, estradiol, testosterone, and possibly androstenedione and DHEAs, in postmenopausal women are associated with a high risk of subsequent breast cancer.     

Premenopausal serum androgens and breast cancer risk: a nested case-control study

Introduction

Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited.

Methods

A case-control study nested within the New York University Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated.

Results

Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9 to 2.3), 1.2 (95% CI, 0.7 to 1.9), 1.4 (95% CI, 0.9 to 2.3) and 1.8 (95% CI, 1.1 to 2.9; P _trend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7 to 1.8), 1.5 (95% CI, 0.9 to 2.3), 1.5 (95% CI, 0.9 to 2.3), and 1.8 (95% CI, 1.1 to 2.8, P _trend = 0.01). A marginally significant positive association was observed with androstenedione (P = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls).

Conclusions

Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50 years should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.     

Lifetime cumulative number of menstrual cycles and serum sex hormone levels in postmenopausal women

Objective Lifetime cumulative number of menstrual cycles is related to breast cancer risk. The aim of this study is to investigate the relation between this index and serum sex hormone levels in postmenopausal women. Methods Cross-sectional study including 860 naturally postmenopausal Dutch participants of the European Prospective Investigation into Cancer and Nutrition. Lifetime cumulative number of menstrual cycles was computed using questionnaire data on ages at menarche and menopause, number of pregnancies, breastfeeding, oral contraceptive use (OC) and regularity pattern. Measurements of hormones included estrone (E1), estradiol (E2), andostrenedione, testosterone, sex-hormone binding globulin (SHBG) and dehydroepiandrostenedione sulfate (DHEAS). The relation between the lifetime cumulative number of menstrual cycles and hormone levels was assessed using analysis of covariance. Relations between reproductive characteristics and hormone levels were also studied. Adjustments for characteristics at blood collection included age, years since menopause, BMI, hormone replacement therapy use, OC use, smoking habits, alcohol intake and physical activity were done. Results Lifetime cumulative number of cycles was related with SHBG; participants in the lowest category had higher SHBG levels. For the separate characteristics, DHEAS and androstenedione increased significantly with increasing age at menarche, while androstenedione and testosterone decreased with increasing age at menopause. For the parity characteristics, SHBG levels increased according to the number of live births. Conclusions Lifetime cumulative number menstrual cycles was related only to SHBG. Therefore, free levels of estrogens or androgens may be related to this number of menstrual cycles estimate, reflecting lifetime exposure to ovarian hormones.     

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.

     

Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: A nested case–referent study

According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case–referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case‐index mother pair, three or four matched referent‐referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06–0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2–12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98–1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring. © 2009 UICC     

Racial/ethnic differences in postmenopausal endogenous hormones: the multiethnic cohort study.

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 (E(1)), estradiol (E(2)), 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 < or = 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), E(1) (> or =21%; P = 0.009), total E(2) (+26%, P = 0.001), bioavailable E(2) (+31%, P < 0.001), and lower SHBG (-12% P = 0.07) levels. Compared with Whites, Japanese Americans had higher E(2) (+15%, P = 0.036) and bioavailable E(2) (+18%, P = 0.024) levels. African Americans also had higher E(1) (+21%, P = 0.004), E(2) (+20%, P = 0.007), and bioavailable E(2) (+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.     

Relation of demographic factors,menstrual history,reproduction and medication use to sex hormone levels in postmenopausal women

In postmenopausal women, levels of estrogens, androgens, and perhaps prolactin have been related to risk of breast and other hormonal cancers in women. However, the determinants of these hormone concentrations have not been firmly established. Associations among various demographic, menstrual, and reproductive factors, medication use and endogenous sex hormone concentrations (estradiol, free estradiol, estrone, estrone sulfate, testosterone, free testosterone, sex hormone binding globulin, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), dihydrotestosterone, and prolactin) were evaluated in a cross-sectional analysis from a simple random sample of 274 postmenopausal women selected from the Women’s Health Initiative Dietary Modification Trial. In multiple regression analyses on log-transformed hormones, the concentrations of DHEA, and DHEAS were negatively and statistically significantly associated with age (both β = −0.03, P < 0.001, respectively). Estradiol, estrone, DHEA, and free testosterone concentrations were higher in African-American than in non-Hispanic White women, but after multivariate adjustment the associations were statistically significant only for free testosterone (β = 0.38, P = 0.01). Women who had a history of bilateral oophorectomy had a mean 35% lower testosterone concentration compared with women with at least one ovary remaining (β = −0.43, P = 0.002), and lower free testosterone (β = −0.42, P = 0.04) after multivariate adjustment. Women who reported regular use of NSAIDs had higher DHEA concentrations (β = 0.20, P = 0.04) and lower prolactin concentrations (β = −0.18, P = 0.02) compared with non-users. These results suggest that while age, oophorectomy status, and NSAID use may be associated with selected sex hormone concentrations, few menstrual or reproductive factors affect endogenous sex hormones in the postmenopausal period.     

The association of plasma androgen levels with breast,ovarian and endometrial cancer risk factors among postmenopausal women

Although androgens may play an etiologic role in breast, ovarian and endometrial cancers, little is known about factors that influence circulating androgen levels. We conducted a cross‐sectional analysis among 646 postmenopausal women in the Nurses' Health Study to examine associations between adult risk factors for cancer, including the Rosner/Colditz breast cancer risk score, and plasma levels of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). All analyses were adjusted for age, laboratory batch and other cancer risk factors. Free testosterone levels were 79% higher among women with a body mass index of ≥30 vs. <22 kg/m² (p‐trend <0.01) and 25% higher among women with a waist circumference of >89 vs. ≤74 cm (p‐trend = 0.02). Consuming >30 g of alcohol a day vs. none was associated with a 31% increase in DHEA and 59% increase in DHEAS levels (p‐trend = 0.01 and <0.01, respectively). Smokers of ≥25 cigarettes per day had 35% higher androstenedione and 44% higher testosterone levels than never smokers (p‐value, F‐test = 0.03 and 0.01, respectively). No significant associations were observed for height or time since menopause with any androgen. Testosterone and free testosterone levels were ～30% lower among women with a hysterectomy vs. without (both p‐values < 0.01). Overall breast cancer risk was not associated with any of the androgens. Thus, several risk factors, including body size, alcohol intake, smoking and hysterectomy, were related to androgen levels among postmenopausal women, while others, including height and time since menopause, were not. Future studies are needed to clarify further which lifestyle factors modulate androgen levels.     

Androgens and musculoskeletal symptoms among breast cancer patients on aromatase inhibitor therapy

Aromatase inhibitors (AIs), the adjuvant hormonal treatment of choice for postmenopausal estrogen receptor-positive breast cancer, are associated with an increased risk of musculoskeletal symptoms. The underlying cause of the symptoms is often attributed to estrogen depletion, yet all women treated with AIs have low estrogen levels and only a subset develop symptoms. Concentrations of circulating androgens may be mediating factors contributing to these side effects. The purpose of this study was to examine changes in androgen concentrations among women initiating AI therapy and to determine if concentrations are associated with musculoskeletal symptoms. Data were analyzed from a cohort study of 74 breast cancer patients for whom AI therapy was planned. Questionnaire data on symptoms were collected and blood was drawn prior to AI therapy (baseline) and then again at 3 and 6 months after baseline. Blood was assayed for testosterone, androstenedione, dehydroepiandrosterone-sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Free testosterone index (FTI) values were calculated using testosterone and SHBG measurements. The results showed that concentrations of all of the androgens increased over the study period, with statistically significant differences from baseline concentrations observed for the FTI at 3 and 6 months and for DHEAS at 6 months. Additionally, breast cancer patients with new onset or worsening of pain over the study period had a significantly smaller change in mean DHEAS concentration from baseline to 3 months (P = 0.04) and a marginally significant smaller change in mean DHEAS concentration from baseline to 6 months (P = 0.1) compared to those who reported no pain at all time points or no worsening of pain across the study period. Changes in testosterone, androstenedione, and the FTI were not associated with the onset or worsening of pain during the study period. Findings from this study suggest that higher DHEAS concentrations are associated with less AI-associated pain and should be further investigated.     

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.     

Circulating levels of sex steroid hormones and risk of ovarian cancer

Experimental and epidemiological evidence supports a role for sex steroid hormones in the pathogenesis of ovarian cancer. We investigated the association between ovarian cancer risk and pre‐diagnostic blood concentrations of testosterone, androstenedione, DHEAS, estrone and SHBG. A case–control study nested within 3 cohorts, in New York (USA), Umeå (Sweden) and Milan (Italy), included 132 subjects with primary invasive epithelial ovarian cancer. For each case subject, 2 controls were selected who matched a case on cohort, menopausal status, age and date of recruitment and, if premenopausal, day of the menstrual cycle at blood donation. Only women who did not use exogenous hormones at blood donation were included in the study. Conditional logistic regression was used to relate cancer risk to sex steroid hormone concentrations with adjustment for potential confounders. No clear association was observed between ovarian cancer risk and any of the 5 hormones under study. In the premenopausal group, the risk appeared to increase with increasing blood concentrations of androstenedione (upper vs. lower tertile OR = 2.35; 95% CI = 0.81–6.82.), but the small number of subjects in the sub‐group precluded reaching unambiguous conclusions about such association. Our study does not support previous observations relating elevations in blood levels of the major sex steroid hormones to an increased risk of ovarian cancer, but offers some evidence that elevated circulating androstenedione before menopause may be associated with increased ovarian cancer risk. © 2003 Wiley‐Liss, Inc.     

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF‐I and decreased levels of IGF‐binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre‐diagnostic blood concentrations of C‐peptide (a marker of pancreatic insulin production), IGF‐I, IGFBP‐1, ‐2 and ‐3 with endometrial cancer risk. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C‐peptide (p_trend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91–11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65–11.7)]. IGFBP‐1 levels were inversely related to endometrial cancer [p_trend = 0.002; OR in the upper quintile = 0.30 (0.15–0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [p_trend = 0.06; OR in the upper quintile = 0.49 (0.22–1.07)]. Risk was unrelated to levels of IGF‐I, IGFBP‐2 and IGFBP‐3. Chronic hyperinsulinemia, as reflected by increased circulating C‐peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer. © 2003 Wiley‐Liss, Inc.     

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulin-like growth factor 1 (IGF-1) levels among post-menopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p=0.02), free estradiol (p=0.04), total testosterone (p=0.04), free testosterone (p=0.006) and decreased levels of sex hormone-binding globulin (p=0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.     

Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study

We assessed the association of sex hormone levels with breast cancer risk in a case-control study nested within the cohort of 7054 New York University (NYU) Women's Health Study participants who were postmenopausal at entry. The study includes 297 cases diagnosed between 6 months and 12.7 years after enrollment and 563 controls. Multivariate odds ratios (ORs) (95% confidence interval (CI)) for breast cancer for the highest quintile of each hormone and sex-hormone binding globulin (SHBG) relative to the lowest were as follows: 2.49 (1.47-4.21), P(trend)=0.003 for oestradiol; 3.24 (1.87-5.58), P(trend)<0.001 for oestrone; 2.37 (1.39-4.04), P(trend)=0.002 for testosterone; 2.07 (1.28-3.33), P(trend)<0.001 for androstenedione; 1.74 (1.05-2.89), P(trend)<0.001 for dehydroepiandrosterone sulphate (DHEAS); and 0.51 (0.31-0.82), P(trend)<0.001 for SHBG. Analyses limited to the 191 cases who had donated blood five to 12.7 years prior to diagnosis showed results in the same direction as overall analyses, although the tests for trend did not reach statistical significance for DHEAS and SHBG. The rates of change per year in hormone and SHBG levels, calculated for 95 cases and their matched controls who had given a second blood donation within 5 years of diagnosis, were of small magnitude and overall not different in cases and controls. The association of androgens with risk did not persist after adjustment for oestrone (1.08, 95% CI=0.92-1.26 for testosterone; 1.15, 95% CI=0.95-1.39 for androstenedione and 1.06, 95% CI=0.90-1.26 for DHEAS), the oestrogen most strongly associated with risk in our study. Our results support the hypothesis that the associations of circulating oestrogens with breast cancer risk are more likely due to an effect of circulating hormones on the development of cancer than to elevations induced by the tumour. They also suggest that the contribution of androgens to risk is largely through their role as substrates for oestrogen production.     

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.     

Intake of trans fatty acids from partially hydrogenated vegetable and fish oils and ruminant fat in relation to cancer risk

Intake of trans fatty acids (TFA) may influence systemic inflammation, insulin resistance and adiposity, but whether TFA intake influences cancer risk is insufficiently studied. We examined the association between TFA intake from partially hydrogenated vegetable oils (PHVO‐TFA), partially hydrogenated fish oils (PHFO‐TFA), and ruminant fat (rTFA) and cancer risk in the Norwegian counties study, a large cohort study with a participation rate >80%. TFA intake was assessed three times in 1974–1988 by questionnaire. A total of 77,568 men and women were followed up through 2007, during which time 12,004 cancer cases occurred. Hazard ratios (HRs) and confidence intervals (CIs) were estimated with Cox regression for cancer sites with ≥150 cases during follow‐up. Significantly increased or decreased risks were found when comparing the highest and lowest intake categories (HRs, 95% CIs) for PHVO‐TFA and pancreatic cancer in men (0.52, 0.31–0.87) and non‐Hodgkin lymphoma (NHL) in both genders (0.70, 0.50–0.98); PHFO‐TFA and rectal cancer (1.43, 1.09–1.88), prostate cancer (0.82, 0.69–0.96), and multiple myeloma (2.02, 1.24–3.28); and rTFA and all cancers (1.09, 1.02–1.16), cancer of the mouth/pharynx (1.59, 1.08–2.35), NHL (1.47, 1.06–2.04) and multiple myeloma (0.45, 0.24–0.84). Furthermore, positive trends were found for PHFO‐TFA and stomach cancer (p_trend = 0.01) and rTFA and postmenopausal breast cancer (p_trend = 0.03). Inverse trends were found for PHVO‐TFA and all cancers (p_trend = 0.006) and cancer of the central nervous system in women (p_trend = 0.005). PHFO‐TFA, but not PHVO‐TFA, seemed to increase cancer risk. The increased risks observed for rTFA may be linked to saturated fat.